U.S. patent number 5,723,497 [Application Number 08/513,872] was granted by the patent office on 1998-03-03 for amine derivative and dermatologic preparation containing the same.
This patent grant is currently assigned to Kao Corporation. Invention is credited to Taketoshi Fujimori, Tsutomu Fujimura, Kazuhiko Higuchi, Genji Imokawa, Akira Kawamata, Hiroshi Kusuoku, Ayumi Ogawa, Yukihiro Ohashi, Hiroyuki Ohsu, Yoshinori Takema, Yukihiro Yada.
United States Patent |
5,723,497 |
Ohashi , et al. |
March 3, 1998 |
**Please see images for:
( Certificate of Correction ) ** |
Amine derivative and dermatologic preparation containing the
same
Abstract
The present invention relates to an amine derivative represented
by the following general formula (I) or (II): ##STR1## wherein
R.sup.1 means a heteroatom-containing C.sub.1 -C.sub.40 hydrocarbon
group which may have a ring structure, or the like; R.sup.2
-R.sup.5 each denote a C.sub.1 -C.sub.20 hydrocarbon group,
hydrogen or the like; A.sup.1 represents ##STR2## or R.sup.15
--Z--.sup.16 --(CH.sub.2).sub.n --; B.sup.1 stands for hydrogen, a
C.sub.1 -C.sub.10 hydrocarbon group, nitrogen or the like; C.sup.1
denotes hydrogen, a C.sub.1 -C.sub.10 hydrocarbon group, nitrogen,
alcohol residue, phosphoric acid residue or the like; a
dermatologic preparation containing the same; and a process for
producing the amine derivative. This amine derivative has excellent
effects of smoothing or removing wrinkles and improving
keratinization.
Inventors: |
Ohashi; Yukihiro (Utsunomiya,
JP), Yada; Yukihiro (Haga-gun, JP), Takema;
Yoshinori (Haga-gun, JP), Fujimori; Taketoshi
(Haga-gun, JP), Kawamata; Akira (Utsunomiya,
JP), Ohsu; Hiroyuki (Haga-gun, JP),
Higuchi; Kazuhiko (Haga-gun, JP), Imokawa; Genji
(Utsunomiya, JP), Kusuoku; Hiroshi (Haga-gun,
JP), Ogawa; Ayumi (Haga-gun, JP), Fujimura;
Tsutomu (Haga-gun, JP) |
Assignee: |
Kao Corporation (Tokyo,
JP)
|
Family
ID: |
27584161 |
Appl.
No.: |
08/513,872 |
Filed: |
September 18, 1995 |
PCT
Filed: |
March 17, 1994 |
PCT No.: |
PCT/JP94/00436 |
371
Date: |
September 18, 1995 |
102(e)
Date: |
September 18, 1995 |
PCT
Pub. No.: |
WO94/21595 |
PCT
Pub. Date: |
September 29, 1994 |
Foreign Application Priority Data
|
|
|
|
|
Mar 17, 1993 [JP] |
|
|
5-057248 |
Mar 17, 1993 [JP] |
|
|
5-057249 |
Mar 17, 1993 [JP] |
|
|
5-057251 |
Mar 18, 1993 [JP] |
|
|
5-058875 |
Mar 19, 1993 [JP] |
|
|
5-060599 |
Mar 19, 1993 [JP] |
|
|
5-060600 |
Mar 19, 1993 [JP] |
|
|
5-060601 |
Mar 19, 1993 [JP] |
|
|
5-060602 |
Mar 19, 1993 [JP] |
|
|
5-060603 |
Mar 19, 1993 [JP] |
|
|
5-060604 |
Feb 17, 1994 [JP] |
|
|
6-020184 |
Mar 10, 1994 [JP] |
|
|
6-039480 |
Mar 11, 1994 [JP] |
|
|
6-041324 |
|
Current U.S.
Class: |
514/669; 514/670;
514/844; 514/845; 564/507; 514/873; 514/668; 564/506 |
Current CPC
Class: |
A61K
8/41 (20130101); A61K 8/49 (20130101); A61K
8/68 (20130101); A61Q 19/00 (20130101); A61Q
19/08 (20130101); C07C 215/08 (20130101); C07C
215/10 (20130101); C07C 215/12 (20130101); C07C
217/28 (20130101); C07C 219/06 (20130101); C07C
229/12 (20130101); C07C 229/24 (20130101); C07C
233/18 (20130101); C07C 235/10 (20130101); C07C
323/25 (20130101); C07D 295/088 (20130101); C07D
311/58 (20130101); C07D 311/72 (20130101); C07D
317/22 (20130101); C07F 9/091 (20130101); C07H
15/04 (20130101); C07F 7/081 (20130101); C07F
7/0838 (20130101); A61K 8/46 (20130101); Y10S
514/845 (20130101); A61Q 17/04 (20130101); Y10S
514/873 (20130101); Y10S 514/844 (20130101) |
Current International
Class: |
C07C
229/12 (20060101); C07C 219/00 (20060101); C07C
229/00 (20060101); C07C 215/12 (20060101); C07C
217/28 (20060101); C07C 215/10 (20060101); C07C
215/08 (20060101); C07C 229/24 (20060101); C07C
217/00 (20060101); C07C 215/00 (20060101); C07C
219/06 (20060101); C07C 233/00 (20060101); C07C
235/10 (20060101); C07C 323/25 (20060101); C07C
233/18 (20060101); C07C 323/00 (20060101); C07C
235/00 (20060101); A61K 8/68 (20060101); C07D
317/22 (20060101); C07D 311/00 (20060101); C07D
311/72 (20060101); C07D 311/58 (20060101); A61K
8/30 (20060101); C07D 317/00 (20060101); C07F
7/08 (20060101); C07F 7/00 (20060101); C07F
9/09 (20060101); C07D 295/00 (20060101); C07D
295/088 (20060101); C07F 9/00 (20060101); C07H
15/00 (20060101); C07H 15/04 (20060101); A61K
031/13 () |
Field of
Search: |
;564/506,507
;514/669,670,668,844,845,873 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Burn; Brian M.
Attorney, Agent or Firm: Oblon, Spivak, McClelland, Maier
& Neustadt, P.C.
Claims
We claim:
1. A method of smoothing or removing wrinkles, which comprises
applying, to the skin, an amine derivative represented by the
following general formula (I) or (II): ##STR136## wherein R.sup.1
means a hydrocarbon group having 1-3 carbon atoms or a
heteroatom-containing hydrocarbon group having 1-40 carbon atoms,
which may have a ring structure, and R.sup.2, R.sup.3, R.sup.4,
R.sup.5 and R.sup.6 are identical with or different from one
another and denote individually a hydrogen atom or a hydrocarbon
group having 1-20 carbon atoms, which may have at least one
hydroxyl group, ##STR137## wherein A.sup.1 means ##STR138##
[R.sup.7 means a hydrogen atom, a hydrocarbon group having 1-40
carbon atoms, which may have a hydroxyl, carboxyl, alkoxyl,
alkylthio, acylamino or acyloxy group, or --R.sup.10 --Y (R.sup.10
denotes a linear or branched hydrocarbon group having 8-40 carbon
atoms, which may have a hydroxyl group, and Y is --OR.sup.11,
--COOR.sup.12 or ##STR139## (R.sup.11, R.sup.12, R.sup.13 and
R.sup.14 each mean a hydrogen atom or a hydrocarbon group having
1-20 carbon atoms, which may contain an oxygen atom)), R.sup.8
denotes a hydrogen atom or a hydrocarbon group having 1-40 carbon
atoms, which may have a hydroxyl, carboxyl, alkoxyl, alkylthio,
acylamino or acyloxy group, R.sup.9 stands for a hydrogen atom, a
hydrocarbon group having 1-40 carbon atoms, which may have a
hydroxyl, carboxyl, alkoxyl, alkylthio, acylamino or acyloxy group,
a carboxyl group, or ##STR140## and X is a hydrogen atom, hydroxyl
group or ##STR141## [R.sup.15 denotes a linear, branched or cyclic
hydrocarbon group having 1-40 carbon atoms, which may have a
heteroatom, R.sup.16 means a hydrocarbon group having 1-7 carbon
atoms, which may have a hydroxyl or alkoxyl group or ##STR142## Z
denotes --COO--, --O--, --S-- or --CONR.sup.17 (R.sup.17 is a
hydrogen atom or a hydrocarbon group having 1-10 carbon atoms,
which may have a hydroxyl group), and n stands for an integer of
1-5]; B.sup.1 denotes a hydrogen atom, a hydrocarbon group having
1-10 carbon atoms, which may have a hydroxyl group, or a nitrogen
atom; and C.sup.1 stands for a hydrogen atom, a hydrocarbon group
having 1-10 carbon atoms, which may have a hydroxyl group, alkoxyl
group, hydroxyalkyloxy group, phosphoric acid residue, carboxyl
group or alkoxycarbonyl group, a nitrogen atom, or --R.sup.18
--O--X' [R.sup.18 means a hydrocarbon group having 2-10 carbon
atoms, which may have a hydroxyl group, and X' denotes a hydrogen
atom or ##STR143## and B.sup.1 and C.sup.1 may form a heterocyclic
ring, which may contain an oxygen atom, together with the adjacent
nitrogen atom, or an acid-added salt or quaternized product
thereof.
2. The method of smoothing or removing wrinkles according to claim
1, wherein the amine derivative is represented by the following
general formula (Ia): ##STR144## wherein R.sup.21 means a linear or
branched hydrocarbon group having 7-40 carbon atoms and containing
a heteroatom, R.sup.22, R.sup.23, R.sup.24, R.sup.25 and R.sup.26
are identical with or different from one another and denote
individually a hydrogen atom or a hydrocarbon group having 1-10
carbon atoms, which may have one or more hydroxyl groups.
3. The method of smoothing or removing wrinkles according to claim
1, wherein the amine derivative is represented by the following
general formula (Ib): ##STR145## wherein R.sup.27 means a
hydrocarbon group having 7-40 carbon atoms, which has a ring
structure and contains a heteroatom, and R.sup.28, R.sup.29,
R.sup.30, R.sup.31 and R.sup.32 are identical with or different
from one another and denote individually a hydrogen atom or a
hydrocarbon group having 1-10 carbon atoms, which may be
substituted by a hydroxyl group.
4. The method of smoothing or removing wrinkles according to claim
1, wherein the amine derivative is represented by the following
general formula (Ic): ##STR146## wherein R.sup.33 means a
hydrocarbon group having 1-3 carbon atoms or a
heteroatom-containing hydrocarbon group having 1-5 carbon atoms,
and R.sup.34, R.sup.35, R.sup.36, R.sup.37 and R.sup.38 are
identical with or different from one another and denote
individually a hydrogen atom or a hydrocarbon group having 1-20
carbon atoms, which may be substituted by at least one hydroxyl
group.
5. The method of smoothing or removing wrinkles according to claim
1, wherein the amine derivative is represented by the following
general formula (IIa) or (IIb): ##STR147## wherein R.sup.39 means a
linear, branched or cyclic hydrocarbon group having 1-40 carbon
atoms, which may contain a heteroatom, R.sup.40 and R.sup.41 are
identical with or different from each other and denote individually
a divalent hydrocarbon group having 1-3 carbon atoms, R.sup.42
represents a hydrogen atom or a hydrocarbon group having 1-3 carbon
atoms, R.sup.43 stands for a hydrogen atom or a hydrocarbon group
having 1-3 carbon atoms or ##STR148## R.sup.44 is a hydrogen atom
or a hydrocarbon group having 1-10 carbon atoms, which may have one
or more hydroxyl groups, R.sup.45 and R.sup.46 are identical with
or different from each other and represent individually a
hydrocarbon group having 1-3 carbon atoms, which may have 1-3
hydroxyl groups, and Y.sup.1 means a hydrocarbon group having 1-10
carbon atoms and containing one or more groups selected from the
group consisting of a hydroxyl group, alkoxyl group,
hydroxyalkyloxy group, phosphoric acid residue, carboxyl group and
alkoxycarbonyl group, with the proviso that in the formula (IIa),
the case where both R.sup.40 and R.sup.41 are --CH.sub.2 --, both
R.sup.42 and R.sup.43 are hydrogen atoms, and Y.sup.1 is the
following formula: ##STR149## in which R.sup.47, R.sup.48, R.sup.49
and R.sup.50 have the same meaning as R.sup.44, is excluded.
6. The method of smoothing or removing wrinkles according to claim
1, wherein the amine derivative is represented by the following
general formula (IIc): ##STR150## wherein R.sup.51 means a hydrogen
atom or a linear, branched or cyclic hydrocarbon group having 1-40
carbon atoms, R.sup.52 denotes a hydrogen atom or a hydrocarbon
group having 1-5 carbon atoms, which may have one or more hydroxyl
groups, R.sup.53 stands for a hydrogen atom or a hydrocarbon group
having 1-22 carbon atoms, which may have one or more hydroxyl or
alkoxyl groups, R.sup.54 represents a hydrogen atom or a
hydrocarbon group having 1-7 carbon atoms, which may have one or
more hydroxyl groups, R.sup.55 means a hydrogen atom or a
hydrocarbon group having 2-6 carbon atoms, which may have one or
more hydroxyl groups, X.sup.1 denotes a hydrogen atom, hydroxyl
group or ##STR151## and Y.sup.2 represents a hydrogen atom or
##STR152##
7. The method of smoothing or removing wrinkles according to claim
1, wherein the amine derivative is represented by the following
general formula (IId): ##STR153## wherein R.sup.56 means a linear
or branched hydrocarbon group having 8-40 carbon atoms, which may
have a hydroxyl group, R.sup.57, R.sup.58 and R.sup.59 are
identical with or different from each other and denote individually
denotes a hydrogen atom or a hydrocarbon group having 1-7 carbon
atoms, which may have one or more hydroxyl groups, R.sup.60 stands
for a hydrocarbon group having 2-6 carbon atoms, which may have one
or more hydroxyl or alkoxyl groups, X.sup.2 is --OR.sup.61,
--CO.sub.2 R.sup.62 or ##STR154## (R.sup.61, R.sup.62, R.sup.63 and
R.sup.64 are identical with or different from one another and
denote individually a hydrogen atom or a hydrocarbon group having
1-20 carbon atoms, which may contain an oxygen atom), and Y.sup.3
represents a hydrogen atom or a hydroxyl group.
8. The method of smoothing or removing wrinkles according to claim
1, wherein the amine derivative is represented by the following
general formula (IIe): ##STR155## wherein R.sup.65 means a linear,
branched or cyclic hydrocarbon group having 1-40 carbon atoms,
which may contain a heteroatom, R.sup.66 and R.sup.68 are identical
with or different from each other and denote individually a
hydrogen atom or a hydrocarbon group having 1-10 carbon atoms,
which may have a hydroxyl group, R.sup.67 stands for a hydrocarbon
group having 2-10 carbon atoms, which may be substituted by a
hydroxyl group, and A represents --CO.sub.2 --, --S-- or
##STR156##
9. The method of smoothing or removing wrinkles according to claim
1, wherein the amine derivative is represented by the following
general formula (IIf): ##STR157## wherein R.sup.69 means a linear,
branched or cyclic hydrocarbon group having 1-40 carbon atoms,
which may contain a heteroatom, R.sup.70 and R.sup.71 are identical
with or different from each other and denote individually a
hydrogen atom or a hydrocarbon group having 1-10 carbon atoms,
which may have one or more hydroxyl groups, R.sup.72 represents a
hydrocarbon group having 2-6 carbon atoms, which may have one or
more hydroxyl groups, and m stands for an integer of 2-6.
10. The method of smoothing or removing wrinkles according to claim
1, wherein the amine derivative is represented by the following
general formula (IIg): ##STR158## wherein R.sup.73 means a linear,
branched or cyclic hydrocarbon group having 1-40 carbon atoms,
which may have a hydroxyl group, ##STR159##
11. The method of smoothing or removing wrinkles according to claim
1, wherein the amine derivative is represented by the following
general formula (IIh): ##STR160## wherein R.sup.74 and R.sup.75
mean individually a hydrogen atom or a hydrocarbon group having
1-40 carbon atoms, which may have a hydroxyl, carboxyl, alkoxyl,
alkylthio, acylamino or acyloxy group, R.sup.76 denotes a hydrogen
atom or a hydrocarbon group having 1-40 carbon atoms, which may
have an alkoxyl, alkylthio, acylamino or acyloxy group, or a
hydrocarbon group having 1-40 carbon atoms, which may have a
hydroxyl or carboxyl group, with the proviso that the total number
of carbon atoms contained in R.sup.74, R.sup.75 and R.sup.76 is at
least 5, and R.sup.77 and R.sup.78 stand individually for a
hydrogen atom, a hydrocarbon group having 1-10 carbon atoms or a
nitrogen atom, or may form a heterocyclic ring, which may contain
an oxygen atom, together with the adjacent nitrogen atom.
12. A method of improving keratinization, which comprises applying,
to the skin, an amine derivative represented by the following
general formula (I) or (II): ##STR161## wherein R.sup.1 means a
hydrocarbon group having 1-3 carbon atoms or a
heteroatom-containing hydrocarbon group having 1-40 carbon atoms,
which may have a ring structure, and R.sup.2, R.sup.3, R.sup.4,
R.sup.5 and R.sup.6 are identical with or different from one
another and denote individually a hydrogen atom or a hydrocarbon
group having 1-20 carbon atoms, which may have at least one
hydroxyl group, ##STR162## wherein A.sup.1 means ##STR163##
[R.sup.7 means a hydrogen atom, a hydrocarbon group having 1-40
carbon atoms, which may have a hydroxyl, carboxyl, alkoxyl,
alkylthio, acylamino or acyloxy group, or --R.sup.10 --Y (R.sup.10
denotes a linear or branched hydrocarbon group having 8-40 carbon
atoms, which may have a hydroxyl group, and Y is --OR.sup.11,
--COOR.sup.12 or ##STR164## (R.sup.11, R.sup.12, R.sup.13 and
R.sup.14 each mean a hydrogen atom or a hydrocarbon group having
1-20 carbon atoms, which may contain an oxygen atom)), R.sup.8
denotes a hydrogen atom or a hydrocarbon group having 1-40 carbon
atoms, which may have a hydroxyl, carboxyl, alkoxyl, alkylthio,
acylamino or acyloxy group, R.sup.9 stands for a hydrogen atom, a
hydrocarbon group having 1-40 carbon atoms, which may have a
hydroxyl, carboxyl, alkoxyl, alkylthio, acylamino or acyloxy group,
a carboxyl group, or ##STR165## and X is a hydrogen atom, hydroxyl
group or ##STR166## [R.sup.15 denotes a linear, branched or cyclic
hydrocarbon group having 1-40 carbon atoms, which may have a
heteroatom, R.sup.16 means a hydrocarbon group having 1-7 carbon
atoms, which may have a hydroxyl or alkoxyl group or ##STR167## Z
denotes --COO--, --O--, --S-- or --CONR.sup.17 (R.sup.17 is a
hydrogen atom or a hydrocarbon group having 1-10 carbon atoms,
which may have a hydroxyl group), and n stands for an integer of
1-5]; B.sup.1 denotes a hydrogen atom, a hydrocarbon group having
1-10 carbon atoms, which may have a hydroxyl group, or a nitrogen
atom; and C.sup.1 stands for a hydrogen atom, a hydrocarbon group
having 1-10 carbon atoms, which may have a hydroxyl group, alkoxyl
group, hydroxyalkyloxy group, phosphoric acid residue, carboxyl
group or alkoxycarbonyl group, a nitrogen atom, or --R.sup.18
--O--X' [R.sup.18 means a hydrocarbon group having 2-10 carbon
atoms, which may have a hydroxyl group, and X' denotes a hydrogen
atom or ##STR168## and B.sup.1 and C.sup.1 may form a heterocyclic
ring, which may contain an oxygen atom, together with the adjacent
nitrogen atom, or an acid-added salt or quaternized product
thereof.
13. A dermatologic preparation comprising an amine derivative
represented by the following general formula (I) or (IT):
##STR169## wherein R.sup.1 means a hydrocarbon group having 1-3
carbon atoms or a heteroatom-containing hydrocarbon group having
1-40 carbon atoms, which may have a ring structure, and R.sup.2,
R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are identical with or
different from one another and denote individually a hydrogen atom
or a hydrocarbon group having 1-20 carbon atoms, which may have at
least one hydroxyl group, ##STR170## wherein A.sup.1 means
##STR171## [R.sup.7 means a hydrogen atom, a hydrocarbon group
having 1-40 carbon atoms, which may have a hydroxyl, carboxyl,
alkoxyl, alkylthio, acylamino or acyloxy group, or --R.sup.10 --Y
(R.sup.10 denotes a linear or branched hydrocarbon group having
8-40 carbon atoms, which may have a hydroxyl group, and Y is
--OR.sup.11, --COOR.sup.12 or ##STR172## (R.sup.11, R.sup.12,
R.sup.13 and R.sup.14 each mean a hydrogen atom or a hydrocarbon
group having 1-20 carbon atoms, which may contain an oxygen atom)),
R.sup.8 denotes a hydrogen atom or a hydrocarbon group having 1-40
carbon atoms, which may have a hydroxyl, carboxyl, alkoxyl,
alkylthio, acylamino or acyloxy group, R.sup.9 stands for a
hydrogen atom, a hydrocarbon group having 1-40 carbon atoms, which
may have a hydroxyl, carboxyl, alkoxyl, alkylthio, acylamino or
acyloxy group, a carboxyl group, or ##STR173## and X is a hydrogen
atom, hydroxyl group or ##STR174## [R.sup.15 denotes a linear,
branched or cyclic hydrocarbon group having 1-40 carbon atoms,
which may have a heteroatom, R.sup.16 means a hydrocarbon group
having 1-7 carbon atoms, which may have a hydroxyl or alkoxyl group
or ##STR175## Z denotes --COO--, --O--, --S-- or --CONR.sup.17
(R.sup.17 is a hydrogen atom or a hydrocarbon group having 1-10
carbon atoms, which may have a hydroxyl group), and n stands for an
integer of 1-5]; B.sup.1 denotes a hydrogen atom, a hydrocarbon
group having 1-10 carbon atoms, which may have a hydroxyl group, or
a nitrogen atom; and C.sup.1 stands for a hydrogen atom, a
hydrocarbon group having 1-10 carbon atoms, which may have a
hydroxyl group, alkoxyl group, hydroxyalkyloxy group, phosphoric
acid residue, carboxyl group or alkoxycarbonyl group, a nitrogen
atom, or --R.sup.18 --O--X' [R.sup.18 means a hydrocarbon group
having 2-10 carbon atoms, which may have a hydroxyl group, and X'
denotes a hydrogen atom or ##STR176## and B.sup.1 and C.sup.1 may
form a heterocyclic ring, which may contain an oxygen atom,
together with the adjacent nitrogen atom, or an acid-added salt or
quaternized product thereof.
14. An amine derivative represented by the following general
formula (Ia'): ##STR177## wherein R.sup.21' means a hydrocarbon
group having 8-22 carbon atoms and a hydroxyl or alkoxyl group on
its carbon chain, R.sup.22', R.sup.23' and R.sup.24' are identical
with or different from one another and denote individually a
hydrogen atom, or a methyl, hydroxymethyl or 2-hydroxyethyl group,
and R.sup.25' and R.sup.26' stand for a hydrogen atom, or an
acid-added salt thereof.
15. An amine derivative represented by the following general
formula (Ib'): ##STR178## wherein R.sup.27' means a tocopheryl or
9,10-(isopropylidenedioxy)octadecyl group, and R.sup.28',
R.sup.29', R.sup.30', R.sup.31' and R.sup.32' are identical with or
different from one another and denote individually a hydrogen atom
or a hydrocarbon group having 1-10 carbon atoms, which may be
substituted by a hydroxyl group, or an acid-added salt thereof.
16. An amine derivative represented by the following general
formula (lId'): ##STR179## wherein R.sup.56' means a linear or
branched hydrocarbon group having 8-40 carbon atoms, R.sup.57',
R.sup.58' and R.sup.59' are identical with or different from one
another and denote individually a hydrogen atom or a hydrocarbon
group having 1-7 carbon atoms, which may have one or more hydroxyl
groups, R.sup.60' is a hydrocarbon group having 2-6 carbon atoms,
which may have one or more hydroxyl groups, X.sup.2' stands for
--OR.sup.61', --CO.sub.2 OR.sup.62' or ##STR180## (R.sup.61',
R.sup.62', R.sup.63' and R.sup.64' are identical with or different
from one another and denote individually a hydrogen atom or a
hydrocarbon group having 1-20 carbon atoms, which may contain an
oxygen atom), and Y.sup.3' means a hydroxyl group, or an acid-added
salt thereof.
17. An amine derivative represented by the following general
formula (IId"): ##STR181## wherein R.sup.56" means an
undecamethylene, dodecamethylene, tridecamethylene or
tetradecamethylene group, R.sup.57", R.sup.58" and R.sup.59" denote
individually a hydrocarbon group having 1-7 carbon atoms, which may
have one or more hydroxyl groups, R.sup.60" is a hydrocarbon group
having 2-6 carbon atoms, which may have one or more hydroxyl
groups, X.sup.2' stands for a hydroxyl group, and Y.sup.3' means a
hydrogen atom, or an acid-added salt thereof.
18. An amine derivative represented by the following general
formula (IIe'): ##STR182## wherein R.sup.65' means a linear or
branched hydrocarbon group having 7-24 carbon atoms and containing
an oxygen atom, R.sup.66' and R.sup.68' denote individually a
hydrogen atom or a hydrocarbon group having 1-10 carbon atoms,
which may be substituted by a hydroxyl group, R.sup.67' stands for
a hydrocarbon group having 2-10 carbon atoms, which may be
substituted by a hydroxyl group, and A represents --CO.sub.2 --,
##STR183## or an acid-added salt thereof.
19. The amine derivative of claim 14, which is a member selected
from the group consisting of ##STR184##
20. The amine derivative of claim 14, which is a member selected
from the group consisting of ##STR185## wherein R is hydrogen,
methyl or 2-hydroxyethyl and R' is hydrogen or methyl.
21. The amine derivative of claim 14, which is ##STR186##
22. The amine derivative of claim 14, which is
1-(2hydroxyethylamino)-3-(12-hydroxyoctadecyloxy)-2-propanol.
Description
This application is a 35USC371 of PCT/JP94/00436, filed Mar. 17,
1994.
1. Technical Field
The present invention relates to an amine derivative which has
excellent effects of preventing and smoothing or removing wrinkles,
makes it possible to maintain the normal functions of the skin and
moreover is useful for the prevention of dandruff and in improving
the skin after sunburn, and an external skin care preparation
(hereinafter referred to as "a dermatologic preparation")
containing such an amine derivative.
2. Background Art
In recent years, it has been a matter of significant concern to
maintain a healthy and beautiful skin irrespective of age or sex.
However, the skin is delicately affected by temperature, humidity,
ultraviolet rays, cosmetic compositions, aging, diseases, stress,
eating habits and the like. Therefore, various troubles such as the
decrement of various functions (functions of preventing the loss of
water and the like from the vital body, controlling the homeostatic
maintenance of the body heat, protecting the body from physical and
chemical stimulation and various bacteria and keeping the
resilience of the skin to determine its surface form, and the like)
of the skin and aging of the skin occur.
Of these, wrinkles, which are one of dermal troubles, occur due to
aging or dermal aging by sunlight. More specifically, cells for
producing the fibrous tissue of the dermis are made small and
lessened by exposure to sunlight or with the increase in age, and
particularly, collagen fibers are lost to a great extent, and so
the skin is aged by degeneration of the dermis, reduction of
subcutaneous adipose tissue and the like, which forms the cause of
wrinkles, relaxation and loss of resilience.
Various compositions and methods have heretofore been proposed for
preventing or removing wrinkles caused by such an aging effect
(Japanese Patent Application Laid-Open Nos. 185005/1987,
502546/1987, 72157/1990 and 288822/1990, etc.).
However, all of these proposals have not exhibited a satisfactory
effect of preventing or smoothing wrinkles.
On the other hand, vulgaris cutaneous troubles such as xeroderma,
fatty skin and seborrhea sicca in epidermis occur due to the
functional aberration of skin tissue caused by intracorporeal and
extracorporeal factors, which act on the vital body, such as
changes of external environment (seasonal changes, ultraviolet
rays, etc.) and variations in physiological functions (attendant on
aging or a disease), dermal hypertrophy and parakeratosis induced
thereby, etc.
In order to prevent and improve such cutaneous troubles, it has
been attempted, for example, to apply a synthetic or natural
humectant to the skin, thereby preventing the drying of the skin
and enhancing the moistening ability of the skin, or to apply a
blood-circulation-accelerating agent to the skin, thereby
accelerating the circulation of blood.
However, these methods have involved various problems in respect of
the preventing and improving effects on the various cutaneous
troubles, persistency thereof, stability and safety of the agents
used, and the like. That is, since these methods generally are
intended to supply the water of the surface of the epidermis, in
particular, of the horny layer, or a part of the humectant, the
efficacy and effect thereof have been temporary, and so persistent
improvement of the skin has been unable to be expected.
There has thus been a demand for development of a substance having
excellent effects of preventing the occurrence of wrinkles and
smoothing or removing the wrinkles and on the other hand,
possessing marked inhibitory effects on parakeratosis of the skin,
dermal hypertrophy, metabolic aberration of lipid and the like.
In view of the foregoing circumstances, the present inventors have
carried out an extensive investigation. As a result, it has been
found that a specific amine derivative, which will be described
subsequently, exhibits marked effects of smoothing or removing
wrinkles and improving keratinization, thus leading to completion
of the present invention.
DISCLOSURE OF THE INVENTION
The present invention is directed to a method of smoothing or
removing wrinkles, which comprises applying, to the skin, an amine
derivative represented by the following general formula (I) or
(II): ##STR3## wherein R.sup.1 means a hydrocarbon group having 1-3
carbon atoms or a heteroatom-containing hydrocarbon group having
1-40 carbon atoms, which may have a ring structure, and R.sup.2,
R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are identical with or
different from one another and denote individually a hydrogen atom
or a hydrocarbon group having 1-20 carbon atoms, which may have at
least one hydroxyl group, ##STR4## wherein A.sup.1 means ##STR5##
[R.sup.7 means a hydrogen atom, a hydrocarbon group having 1-40
carbon atoms, which may have a hydroxyl, carboxyl, alkoxyl,
alkylthio, acylamino or acyloxy group, or --R.sup.10 --Y (R.sup.10
denotes a linear or branched hydrocarbon group having 8-40 carbon
atoms, which may have a hydroxyl group, and Y is --OR.sup.11,
--COOR.sup.12 or ##STR6## (R.sup.11, R.sup.12, R.sup.13 and
R.sup.14 each mean a hydrogen atom or a hydrocarbon group having
1-20 carbon atoms, which may contain an oxygen atom)), R.sup.8
denotes a hydrogen atom or a hydrocarbon group having 1-40 carbon
atoms, which may have a hydroxyl, carboxyl, alkoxyl, alkylthio,
acylamino or acyloxy group, R.sup.9 stands for a hydrogen atom, a
hydrocarbon group having 1-40 carbon atoms, which may have a
hydroxyl, carboxyl, alkoxyl, alkylthio, acylamino or acyloxy group,
a carboxyl group, or ##STR7## and X is a hydrogen atom, hydroxyl
group or ##STR8## [R.sup.15 denotes a linear branched or cyclic
hydrocarbon group having 1-40 carbon atoms, which may have a
heteroatom, R.sup.16 means a hydrocarbon group having 1-7 carbon
atoms, which may have a hydroxyl or alkoxyl group or ##STR9## Z
denotes --COO--, --O--, --S-- or --CONR.sup.17 (R.sup.17 is a
hydrogen atom or a hydrocarbon group having 1-10 carbon atoms,
which may have a hydroxyl group), and n stands for an integer of
1-5]; B.sup.1 denotes a hydrogen atom, a hydrocarbon group having
1-10 carbon atoms, which may have a hydroxyl group, or a nitrogen
atom; and C.sup.1 stands for a hydrogen atom, a hydrocarbon group
having 1-10 carbon atoms, which may have a hydroxyl group, alkoxyl
group, hydroxyalkyloxy group, phosphoric acid residue, carboxyl
group or alkoxycarbonyl group, a nitrogen atom, or --R.sup.18
--O--X' [R.sup.18 means a hydrocarbon group having 2-10 carbon
atoms, which may have a hydroxyl group, and X' denotes a hydrogen
atom or ##STR10## and B.sup.1 and C.sup.1 may form a heterocyclic
ring, which may contain an oxygen atom, together with the adjacent
nitrogen atom, or an acid-added salt or quaternized product
thereof.
The present invention is also directed to a method of improving
keratinization, which comprises applying the amine derivative
represented by the general formula (I) or (II), or an acid-added
salt or quaternized product thereof to the skin.
The present invention is further directed to a dermatologic
preparation comprising the amine derivative represented by the
general formula (I) or (II), or an acid-added salt or quaternized
product thereof.
The present invention is still further directed to an amine
derivative represented by the following general formula (Ia'):
##STR11## wherein R.sup.21' means a hydrocarbon group having 8-22
carbon atoms and a hydroxyl or alkoxyl group on its carbon chain,
R.sup.22', R.sup.23' and R.sup.24' are identical with or different
from one another and denote individually a hydrogen atom, or a
methyl, hydroxymethyl or 2-hydroxyethyl group, and R.sup.25' and
R.sup.26' stand for a hydrogen atom, or an acid-added salt
thereof.
The present invention is yet still further directed to an amine
derivative represented by the following general formula (Ib'):
##STR12## wherein R.sup.27' means a tocopheryl or
9,10-(isopropylidenedioxy)octadecyl group, and R.sup.28',
R.sup.29', R.sup.30', R.sup.31' and R.sup.32' are identical with or
different from one another and denote individually a hydrogen atom
or a hydrocarbon group having 1-10 carbon atoms, which may be
substituted by a hydroxyl group, or an acid-added salt thereof.
The present invention is yet still further directed to an amine
derivative represented by the following general formula (IId'):
##STR13## wherein R.sup.56' means a linear or branched hydrocarbon
group having 8-40 carbon atoms, R.sup.57', R.sup.58' and R.sup.59'
are identical with or different from one another and denote
individually a hydrogen atom or a hydrocarbon group having 1-7
carbon atoms, which may have one or more hydroxyl groups, R.sup.60'
is a hydrocarbon group having 2-6 carbon atoms, which may have one
or more hydroxyl groups, X.sup.2' stands for --OR.sup.61',
--CO.sub.2 OR.sup.62' or ##STR14## (R.sup.61', R.sup.62', R.sup.63'
and R.sup.64' are identical with or different from one another and
denote individually a hydrogen atom or a hydrocarbon group having
1-20 carbon atoms, which may contain an oxygen atom), and Y.sup.3'
means a hydroxyl group, or an acid-added salt thereof.
The present invention is yet still further directed to an amine
derivative represented by the following general formula (IId"):
##STR15## wherein R.sup.56" means an undecamethylene,
dodecamethylene, tridecamethylene or tetradecamethylene group,
R.sup.57", R.sup.58" and R.sup.59" denote individually a
hydrocarbon group having 1-7 carbon atoms, which may have one or
more hydroxyl groups, R.sup.60" is a hydrocarbon group having 2-6
carbon atoms, which may have one or more hydroxyl groups, X.sup.2'
stands for a hydroxyl group, and y.sup.3' means a hydrogen atom, or
an acid-added salt thereof.
The present invention is yet still further directed to an amine
derivative represented by the following general formula (IIe'):
##STR16## wherein R.sup.65' means a linear or branched hydrocarbon
group having 7-24 carbon atoms and containing an oxygen atom,
R.sup.66' and R.sup.68' denote individually a hydrogen atom or a
hydrocarbon group having 1-10 carbon atoms, which may be
substituted by a hydroxyl group, R.sup.67' stands for a hydrocarbon
group having 2-10 carbon atoms, which may be substituted by a
hydroxyl group, and A represents --CO.sub.2 --, --S-- or ##STR17##
or an acid-added salt thereof.
BEST MODE FOR CARRYING OUT THE INVENTION
The amine derivatives useful in the practice of the present
invention are represented by the general formula (I) or (II).
In the general formula (I), the hydrocarbon groups represented by
R.sup.1 -R.sup.6 may be either saturated or unsaturated, and any of
linear, branched and cyclic hydrocarbon groups. In R.sup.1, the
hydrocarbon groups having 1-3 carbon atoms include alkyl or alkenyl
groups having 1-3 carbon atoms, specifically, methyl, ethyl,
propyl, isopropyl and allyl. In the heteroatom-containing
hydrocarbon groups in R.sup.1, which have 1-40 carbon atoms and may
have a ring structure, examples of the heteroatoms contained in
these groups include oxygen, nitrogen, silicon, fluorine, chlorine,
bromine, iodine, sulfur and phosphorus atoms. Of these, oxygen,
nitrogen, silicon and fluorine atoms are preferred. The
heteroatom-containing hydrocarbon groups each have a structure that
one or more hydrogen atoms of a hydrocarbon group containing no
heteroatom have been substituted by the corresponding number of
heteroatoms and/or heteroatom-containing atomic groups. Examples of
the atomic groups include hydroxyl, alkoxyl, carboxyl,
alkoxycarbonyl, acylamino, acyl, acyloxy, alkoxycarbonyloxy,
aminocarbonyloxy, amino, alkylsilyl, mercapto, alkylthio, sulfonyl,
sulfonyloxy and phosphoryloxy groups. Of these, hydroxyl, alkoxyl,
carboxyl, alkoxycarbonyl, acylamino and alkylsilyl group are
preferred.
Examples of the hydrocarbon moiety containing no heteroatom include
hydrocarbon groups such as octyl, nonyl, decyl, undecyl, dodecyl,
tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl,
dotriacontyl, 2-ethylhexyl and 9-octadecenyl.
These hydrocarbon groups represented by R.sup.1 may have a ring
structure. Such a hydrocarbon group may be either a group composed
of only a ring structure or a group partially having a ring
structure. The ring structure may be any of alicyclic, aromatic and
heterocyclic rings. Examples thereof include benzene, pyran,
tetrahydropyran, furan, tetrahydrofuran, dioxolane and dioxane.
Preferable specific examples of the heteroatom-containing
hydrocarbon groups and the hydrocarbon groups having a ring
structure in R.sup.1 include groups such as 2-hydroxyethyl,
3-hydroxypropyl, 2,3-dihydroxypropyl,
2,2-bis(hydroxymethyl)-3-hydroxypropyl, carboxymethyl,
aminocarbonylmethyl, 1-(N,N-dimethylamino)ethyl,
12-hydroxyoctadecyl, 12-hydroxydodecyl, 9-hydroxynonyl,
9,10-dihydroxyoctadecyl, 12-hydroxy-9-octadecenyl,
12-methoxy-octadecyl, 10-(2-ethylhexyloxy)decyl, 11-carboxyundecyl,
11-butoxycarbonylundecyl, 11-(2-ethylhexanoylamino)undecyl,
11-(butyldimethylsilyl)undecyl, tocopheryl, 4-dodecyloxyphenyl,
4-(9-hydroxynonyloxy)phenyl, 9-(4-butoxyphenyloxy)nonyl,
4-(dodecylaminocarbonyl)phenyl,
11-(cyclohexanecarbonylamino)undecyl,
11-(phenyldimethylsilyl)undecyl and
9,10-(isopropylidenedioxy)octadecyl.
In the general formula (I), examples of R.sup.2, R.sup.3, R.sup.4,
R.sup.5 and R.sup.6 include a hydrogen atom and hydrocarbon groups
which have 1-20 carbon atoms, preferably 1-5 carbon atoms and may
be substituted by 1-5 hydroxyl groups. Preferable specific examples
thereof include a hydrogen atom; alkyl groups having 1-20 carbon
atoms, such as methyl, ethyl, butyl, hexyl, tetradecyl and
octadecyl; aryl groups such as phenyl; aralkyl groups such as
benzyl; and alkyl groups substituted by 1-5 hydroxyl groups, such
as hydroxymethyl, 2-hydroxyethyl, 1,2-dihydroxypropyl,
1,2,3-trihydroxybutyl, 1,2,3,4-tetrahydroxypentyl and
1,2,3,4,5-pentahydroxyhexyl.
These amine derivatives represented by the general formula (I) are
prepared in accordance with various known processes, and no
particular limitation is hence imposed on the preparation processes
thereof. However, they may be prepared, for example, by deriving a
glycidyl ether derivative (IV) from a heteroatom-containing alcohol
(III) and adding an amine (V) to this glycidyl ether derivative as
represented by the following reaction scheme. At this time, if the
heteroatom-containing alcohol (III) has a reactive functional group
such as a hydroxyl, carboxyl or amino group, the reaction may be
carried out after the above functional group is protected by an
appropriate protective group, and deblocking may be finally
conducted to prepare the amine derivative (I). ##STR18## wherein
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 have the
same meaning as defined above.
In R.sup.7, R.sup.8 and R.sup.9 in the general formula (II), the
hydrocarbon groups having 1-40 carbon atoms, which may have a
hydroxyl, carboxyl, alkoxyl, alkylthio, acylamino or acyloxy group
may be either saturated or unsaturated, and any of linear, branched
and cyclic hydrocarbon groups. Specific examples thereof include
groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl,
decyl, dodecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl,
eicosyl, methyl-branched isopalmityl, 4,8,12-trimethyltridecyl,
cyclohexyl, phenyl, benzyl, hydroxymethyl, 1-hydroxyethyl,
1-hydroxypropyl, 1-hydroxybutyl, 1-hydroxypentyl, 1-hydroxydodecyl,
1-hydroxytetradecyl, 1-hydroxypentadecyl, 1-hydroxyhexadecyl,
1-hydroxyheptadecyl, 9-hydroxynonyl, 13-hydroxytridecyl,
14-hydroxytetradecyl, 1,2-dihydroxyethyl, 1,2,3-trihydroxy-propyl,
1,2,3,4-tetrahydroxybutyl, 1,2,3,4,5-pentahydroxypentyl,
methoxymethyl, dodecyloxymethyl, tetradecyloxymethyl,
methyl-branched isostearyloxy-methyl, 4-methyl-3-pentenyl,
1-pentadecenyl, 7-hexadecenyl, 1-heptadecenyl, 1-nonenyl,
1-undecenyl, 1-tridecenyl, 1-nonadecenyl, 11-hydroxyheptadecenyl,
13-hydroxynonadecenyl, 9-methylhexadecyl, 11-methyloctadecenyl,
carboxy, 8-carboxyoctyl, 12-carboxydodecyl, 13-carboxytridecyl,
dodecyloxymethyl, tetradecyloxymethyl, hexadecyloxymethyl,
methyl-branched isostearyloxymethyl, 12-hydroxyoctadecyloxymethyl,
15-hydroxypentadecyloxymethyl, 9-(2-ethylhexyloxy)nonyloxymethyl,
dodecylthiomethyl, tetradecylthiomethyl, dodecanoylaminomethyl,
tetradecanoylaminomethyl, hexadecanoylaminomethyl, methyl-branched
isostearoylaminomethyl, 12-hydroxyoctadecanoylaminomethyl,
15-hydroxypentadecanoylaminomethyl,
16-hydroxyhexadecanoylaminomethyl,
12-(2-ethylhexyloxy)dodecanoylaminomethyl,
11-(2-ethylhexanoylamino)undecanoylaminomethyl,
dodecanoyloxymethyl, tetradecanoyloxymethyl, methyl-branched
isostearoyloxymethyl and 2-ethylhexyloxymethyl.
The linear or branched divalent hydrocarbon group having 8-40
carbon atoms indicated by R.sup.10, which may have a hydroxyl
group, may be either saturated or unsaturated. Specific examples
thereof include groups such as octamethylene, nonamethylene,
decamethylene, undecamethylene, dodecamethylene, tridecamethylene,
tetradecamethylene, hexadecamethylene, triacontamethylene,
hexadecane-1,10-diyl, 7-hexadecene-1,10-diyl,
2-hydroxyundecane-1,11-diyl, 2-hydroxytridecane-1,13-diyl and
2-hydroxytetradecane-1,14-diyl.
In R.sup.11, R.sup.12, R.sup.13 and R.sup.14, the hydrocarbon
groups having 1-20 carbon atoms, which may contain an oxygen atom
may be any of linear, branched and cyclic hydrocarbon groups.
Specific examples thereof include groups such as methyl, ethyl,
butyl, hexyl, octyl, dodecyl, hexadecyl, octadecyl, 2-ethylhexyl,
allyl, 2-hydroxyethyl, 2,3-dihydroxypropyl, 2-hydroxypropyl,
6-hydroxyhexyl, 9-hydroxynonyl, 12-hydroxydodecyl, phenyl, benzyl
and tetrahydropyranyl.
In the linear, branched or cyclic hydrocarbon group having 1-40
carbon atoms represented by R.sup.15, which may have a heteroatom,
examples of the heteroatom contained in R.sup.15 include oxygen,
sulfur, nitrogen and silicon atoms. Of these, an oxygen atom is
particularly preferred. The hydrocarbon group of R.sup.15 may be
either saturated or unsaturated. Specific examples thereof include
groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,
octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl,
pentadecyl, heptadecyl, hexadecyl, octadecyl, docosyl,
hentriacontyl, dotriacontyl, methyl-branched isoheptadecyl,
methyl-branched isostearyl, 2-ethylhexyl, 2-heptylundecyl,
5,7,7-trimethyl-2-(1,3,3-trimethylbutyl)octyl, 9-octadecenyl,
9,12-octadecadienyl, cyclohexyl, phenyl, benzyl, cholesteryl,
12-hydroxyoctadecyl, 12-hydroxydodecyl, 9-hydroxynonyl,
9,10-dihydroxyoctadecyl, 12-hydroxy-9-octadecenyl,
12-methoxyoctadecyl, 10-(2-ethylhexyloxy)decyl, 11-carboxyundecyl,
11-butoxycarbonylundecyl, 11-(2-ethylhexanoylamino)undecyl,
11-(butyldimethylsilyl)undecyl, tocopheryl,
9,10-isopropylidenedioxyoctadecyl, hepta-3-yl, heptadeca-8-yl,
8-heptadecenyl, 8,11-heptadecadienyl, 9-decenyl, cyclohexyl,
phenyl, 8-hydroxyoctyl, 11-hydroxyundecyl, 14-hydroxytetradecyl,
15-hydroxypentadecyl, 11-hydroxyheptadecyl,
8,9-dihydroxyheptadecyl, 11-hydroxy-8-heptadecenyl,
11-methoxyheptadecyl, 9-(2-ethylhexyl)nonyl, 10-carboxydecyl,
10-butoxycarbonyldecyl, 10-(2-ethylhexanoylamino)decyl,
10-(butyldimethylsilyl)decyl and
8,9-isopropylidenedioxyheptadecyl.
The hydrocarbon group having 1-7 carbon atoms represented by
R.sup.16, which may have a hydroxyl or alkoxyl group or ##STR19##
may be either linear or branched and saturated or unsaturated.
Specific examples thereof include groups such as methylene,
dimethylene, ethylidene, isopropylidene, hydroxydimethylene and,
##STR20## (R' means a hydrocarbon group having 1-3 carbon atom, R"
denotes a hydrogen atom or a hydrocarbon group having 1-3 carbon
atoms, and R"' is a hydrogen atom, a hydrocarbon group having 1-3
carbon atoms or ##STR21##
In R.sup.17 and B.sup.1, specific examples of the hydrocarbon
groups having 1-10 carbon atoms, which may have a hydroxyl group,
include groups such as methyl, ethyl, butyl, hexyl, phenyl, benzyl,
hydroxyethyl, 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl,
2,3,4,5-tetrahydroxypentyl and 2,3,4,5,6-pentahydroxyhexyl.
In C.sup.1, the hydrocarbon group having 1-10 carbon atoms, which
may have a hydroxyl group, alkoxyl group, hydroxyalkyloxy group,
phosphoric acid residue, carboxyl group or alkoxycarbonyl group,
may be any of linear, branched and cyclic hydrocarbons, and either
saturated or unsaturated. Specific examples thereof include groups
such as methyl, ethyl, propyl, hexyl, cyclohexyl, phenyl, benzyl
and the following groups: ##STR22##
Specific examples of the hydrocarbon group having 2-10 carbon atoms
represented by R.sup.18, which may have a hydroxyl group, include
--(CH.sub.2).sub.2 --, --(CH.sub.2).sub.3 --, --(CH.sub.2).sub.4
--, ##STR23##
Examples of the ring formed by B.sup.1 and C.sup.1 include the
fallowing rings: ##STR24##
These amine derivatives (II) are prepared in accordance with
various known processes, for example, the following reaction
schemes 1 to 11. ##STR25## wherein R.sup.81 means a hydrogen atom,
a hydrocarbon group having 1-40 carbon atoms, which may have a
hydroxyl, carboxyl, alkoxyl, alkylthio, acylamino or acyloxy group,
--R.sup.10 --Y (R.sup.10 and Y having the same meaning as defined
above), R.sup.82 denotes a hydrogen atom or a hydrocarbon group
having 1-40 carbon atoms, which may have a hydroxyl, carboxyl,
alkoxyl, alkylthio, acylamino or acyloxy group, R.sup.83 stands for
a hydrogen atom, a hydrocarbon group having 1-40 carbon atoms,
which may have a hydroxyl, carboxyl, alkoxyl, alkylthio, acylamino
or acyloxy group, or a carboxyl group, R.sup.84 represents a
hydrogen atom or a methyl group, and B.sup.1 and C.sup.1 have the
same meaning as defined above.
Namely, an amine (2) is added to an epoxide (1), thereby obtaining
an amine derivative (II-1). ##STR26## wherein R.sup.39 means a
linear, branched or cyclic hydrocarbon group having 1-40 carbon
atoms, which may have a heteroatom, R.sup.40 denotes a divalent
hydrocarbon group having 1-3 carbon atoms, R.sup.42 represents a
hydrogen atom or a hydrocarbon group having 1-3 carbon atoms,
R.sup.43' stands for a hydrocarbon group having 1-3 carbon atoms,
R.sup.44 is a hydrogen atom or a hydrocarbon group having 1-10
carbon atoms, which may have one or more hydroxyl groups, Y.sup.1'
means a hydrocarbon group having 1-10 carbon atoms and containing
one or more groups selected from the group consisting of hydroxyl,
alkoxyl, hydroxyalkyloxy, carboxyl and alkoxycarbonyl groups, and
R.sup.85 and R.sup.86 denote individually a hydrogen atom or a
methyl group.
Namely, an alcohol (3) is converted to a p-toluenesulfonate (4),
and the resultant p-toluene sulfonate is then reacted with an amine
(2'), thereby obtaining an amine derivative (II-2). ##STR27##
wherein R.sup.41 means --(CH.sub.2).sub..alpha. --(.alpha. is 2 or
3), R.sup.43" denotes a hydrogen atom or a hydrocarbon group having
1-3 carbon atoms, and other groups have the same meaning as defined
above.
Namely, an alcohol (5) is converted to a p-toluenesulfonate (6),
and the resultant p-toluene sulfonate is then reacted with an amine
(2'), thereby obtaining an amine derivative (II-3). ##STR28##
wherein R.sup.39, R.sup.40, R.sup.41, R.sup.42, R.sup.44 and
Y.sup.1' have the same meaning as defined above.
Namely, an amine derivative (II'-4) obtained in Reaction Scheme 1
or 3 is phosphorylated in the presence of a phosphorylating agent
such as POCl.sub.3 or H.sub.3 PO.sub.4, thereby obtaining an amine
derivative (II-4). ##STR29## wherein Z' means a hydrocarbon group
having 1-10 carbon atoms, which may contain one or more of
hydroxyl, alkoxyl, hydroxyalkyloxy, carboxyl and alkoxycarbonyl
groups, and other groups have the same meaning as defined
above.
Namely, an amine derivative (II'-5) obtained in any of Reaction
Schemes 1 to 4 is phosphorylated with a phosphorylating agent such
as POCl.sub.3 or P.sub.2 O.sub.5, thereby obtaining an amine
derivative (II-5). ##STR30## wherein R.sup.45 and R.sup.46 are
identical with or different from each other and mean individually a
hydrocarbon group having 1-3 carbon atoms, which may have 1-3
hydroxyl groups, D.sup.1 denotes a halogen atom, and other groups
have the same meaning as defined above.
Namely, an amine derivative (II'-6) obtained in any of Reaction
Schemes 1 to 5 is quaternized with an alkyl halide (7), thereby
obtaining an amine derivative (II-6). ##STR31## wherein R.sup.87
means a hydrogen atom, a linear, branched or cyclic hydrocarbon
group having 1-40 carbon atoms or X.sup.2 --R.sup.56 --[R.sup.56 is
a linear or branched hydrocarbon group having 8-40 carbon atoms,
which may have a hydroxyl group, and X.sup.2 is --OR.sup.61,
--CO.sub.2 R.sup.62 or ##STR32## (R.sup.61, R.sup.62, R.sup.63 and
R.sup.64 are identical with or different from one another and
denote individually a hydrogen atom or a hydrocarbon group having
1-20 carbon atoms, which may contain an oxygen atom)], R.sup.88 and
R.sup.89 are identical with or different from each other and denote
individually a hydrogen atom or a hydrocarbon group having 1-7
carbon atoms, which may have one or more hydroxyl groups, R.sup.90
stands for a divalent hydrocarbon group having 2-6 carbon atoms,
which may have one or more hydroxyl groups, E.sup.1 represents a
hydrogen atom or a hydroxyl group, and Y.sup.2 is a hydrogen atom
or ##STR33##
Namely, an amide (8) is reduced with LiAlH.sub.2 or the like,
thereby obtaining an amine derivative (II-7). ##STR34## wherein
R.sup.91 means a hydrogen atom, a linear, branched or cyclic
hydrocarbon group having 1-40 carbon atoms or X.sup.2 --R.sup.56
--(X.sup.2 and R.sup.56 have the same meaning as defined above),
R.sup.92, R.sup.93 and R.sup.94 are identical with or different
from one another and denote individually a hydrogen atom or a
hydrocarbon group having 1-7 carbon atoms, which may have one or
more hydroxyl groups, R.sup.95 stands for a divalent hydrocarbon
group having 2-6 carbon atoms, which may have one or more hydroxyl
groups, F.sup.1 represents a hydrogen atom or a hydroxyl group, and
G.sup.1 represents a chlorine, bromine or iodine atom, or
##STR35##
Namely, an amine (2') is added to a compound (10) obtained by
subjecting an alcohol (9) to halogenation or formation of a
sulfonic ester, thereby obtaining an amine derivative (II-8).
##STR36## wherein R.sup.69 means a linear, branched or cyclic
hydrocarbon group having 1-40 carbon atoms, which may contain a
heteroatom, R.sup.69' denotes a lower alkyl group, R.sup.70 and
R.sup.71 are identical with or different from each other and
represent individually a hydrogen atom or a hydrocarbon group
having 1-10 carbon atoms, which may have one or more hydroxyl
groups, R.sup.72 represents a hydrocarbon group having 2-6 carbon
atoms, which may have one or more hydroxyl groups, and m stands for
an integer of 2-6.
Namely, an ester (11) is reacted with an amine (12) in the presence
of a base catalyst, thereby obtaining an amine derivative (II-9).
##STR37## wherein R.sup.74 and R.sup.75 are identical with or
different from each other and mean individually a hydrogen atom or
a hydrocarbon group having 1-40 carbon atoms, which may have a
hydroxyl, carboxyl, alkoxyl, alkylthio, acylamino or acyloxy group,
R.sup.76 denotes a hydrogen atom or a hydrocarbon group having 1-40
carbon atoms, which may have an alkoxyl, alkylthio, acylamino or
acyloxy group, or a hydrocarbon group having 1-40 carbon atoms,
which may have a hydroxyl or carboxyl group, with the proviso that
the total number of carbon atoms contained in R.sup.74, R.sup.75
and R.sup.76 is at least 5, and J.sup.1 stands for a chlorine,
bromine or iodine atom, or ##STR38##
Namely, an epoxide (13), or a halide or sulfonic ester (14) is
reacted with NaN.sub.3 or benzylamine, and the resultant product is
then reduced, thereby obtaining an amine derivative (II-10).
##STR39## wherein R.sup.74' means a lower alkyl group, R.sup.74'
denotes R.sup.74 --CONHCH.sub.2 --, R.sup.77 and R.sup.78 are
identical with or different from each other and represent
individually a hydrogen atom, a hydrocarbon group having 1-10
carbon atoms or a nitrogen atom, or form together a cyclic
hydrocarbon group, which may have an ether oxygen, and other groups
have the same meaning as defined above.
Namely, an ester (18) is reacted with an amine (19), thereby
obtaining an amine derivative (II-11).
In these reactions, if a reactive functional group such as a
carboxyl or hydroxyl group exists in a compound used as a raw
material, the reaction may be carried out after such a functional
group is protected by an appropriate protective group, and
deblocking may be finally conducted to prepare the amine derivative
(II).
Among these amine derivatives (I) or (II), those represented by the
following formulae (Ia)-(Ic) and (IIa)-(IIh) are particularly
preferred. (Ia): ##STR40## wherein R.sup.21 means a linear or
branched hydrocarbon group having 7-40 carbon atoms and containing
a heteroatom, R.sup.22, R.sup.23, R.sup.24, R.sup.25 and R.sup.26
are identical with or different from one another and denote
individually a hydrogen atom or a hydrocarbon group having 1-10
carbon atoms, which may have one or more hydroxyl groups.
Preferable examples of R.sup.22 -R.sup.26 include a hydrogen atom,
alkyl groups having 1-6 carbon atoms and alkyl groups having 1-6
carbon atoms and substituted by 1-5 hydroxyl groups. Particularly
preferable examples thereof include a hydrogen atom, and
hydroxymethyl, 2-hydroxyethyl and 1,2,3,4-tetrahydroxybutyl
groups.
In the general formula (Ia), compounds in which R.sup.21 is a
hydrocarbon group having 8-22 carbon atoms and a hydroxyl or
alkoxyl group on their carbon chains, and R.sup.22 -R.sup.26 are
individually a hydrogen atom or a methyl, hydroxymethyl,
2-hydroxyethyl or 1,2,3,4-tetrahydroxybutyl group are further
preferred. Of these, compounds in which R.sup.21 is a hydrocarbon
group having 8-22 carbon atoms and a hydroxyl or alkoxyl group on
their carbon chains, and R.sup.22 -R.sup.26 are individually a
hydrogen atom; or compounds in which R.sup.21 is a hydrocarbon
group having 8-22 carbon atoms and a hydroxyl or alkoxyl group on
their carbon chains, and R.sup.22 is a methyl or 2-hydroxyethyl
group, and R.sup.23 -R.sup.26 are individually a hydrogen atom are
particularly preferred.
Besides, compounds in which R.sup.21 is a hydrocarbon group having
8-22 carbon atoms and a hydroxyl or alkoxyl group on their carbon
chains, R.sup.22, R.sup.23 and R.sup.24 are individually a hydrogen
atom or a methyl, hydroxymethyl or 2-hydroxyethyl group, and
R.sup.25 and R.sup.26 are individually a hydrogen atom are novel
compounds. Therefore, the present invention also provides such
compounds or acid-added salts thereof. (Ib): ##STR41## wherein
R.sup.27 means a hydrocarbon group having 7-40 carbon atoms, which
has a ring structure and contains a heteroatom, and R.sup.28,
R.sup.29, R.sup.30, R.sup.31 and R.sup.32 are identical with or
different from one another and denote individually a hydrogen atom
or a hydrocarbon group having 1-10 carbon atoms, which may be
substituted by a hydroxyl group.
Examples of the heteroatom contained in R.sup.27 of the amine
derivatives represented by the general formula (Ib) include O, S,
N, Si, etc.
In the general formula (Ib), the hydrocarbon group represented by
R.sup.27 and having a ring structure may be either a group composed
of only a ring structure or a group partially having a ring
structure. The ring structure may be any of alicyclic, aromatic and
heterocyclic rings. Examples thereof include benzene, pyran,
tetrahydropyran, furan, tetrahydrofuran, dioxolane and dioxane.
Groups such as tocopheryl, 4-dodecyloxyphenyl,
4-(9-hydroxynonyloxy)phenyl, 9-(4-butoxyphenyloxy)nonyl,
4-(dodecylamonocarbonyl)phenyl,
11-(cyclohexanecarbonylamino)-undecyl,
11-(phenyldimethylsilyl)undecyl and
9,10-(isopropylidenedioxy)octadecyl are preferred as R.sup.27.
Preferable examples of R.sup.28, R.sup.29, R.sup.30, R.sup.31 and
R.sup.32 include a hydrogen atom and hydrocarbon groups such as
methyl, ethyl, butyl, hexyl, phenyl, benzyl, hydroxymethyl,
hydroxyethyl, 1,2-dihydroxyethyl, 1,2,3-trihydroxypropyl,
1,2,3,4-tetrahydroxybutyl and 1,2,3,4,5-pentahydroxypentyl.
In the general formula (Ib), amine derivatives (Ib') in which
R.sup.27 is a tocopheryl or 9,10-(isopropylidenedioxy)octadecyl
group are novel compounds. Therefore, the present invention also
provides such compounds or acid-added salts thereof. (Ic):
##STR42## wherein R.sup.33 means a hydrocarbon group having 1-3
carbon atoms or a heteroatom-containing hydrocarbon group having
1-5 carbon atoms, and R.sup.34, R.sup.35, R.sup.36, R.sup.37 and
R.sup.38 are identical with or different from one another and
denote individually a hydrogen atom or a hydrocarbon group having
1-20 carbon atoms, which may be substituted by at least one
hydroxyl group.
In the general formula (Ic), examples of the hydrocarbon group
having 1-3 carbon atoms of R.sup.33 include alkyl or alkenyl groups
having 1-3 carbon atoms. Groups such as methyl, ethyl, propyl,
isopropyl and allyl are preferred. Examples of the
heteroatom-containing hydrocarbon group having 1-5 carbon atoms of
R.sup.33 include hydrocarbon groups containing an oxygen atom,
nitrogen atom, silicon atom, sulfur atom, phosphorus atom and/or
fluorine atom. Of these, hydrocarbon groups containing an oxygen
atom and/or nitrogen atom are preferred, with 2-hydroxyethyl,
3-hydroxypropyl, 2,3-dihydroxypropyl,
2,2-bis(hydroxymethyl)-3-hydroxypropyl, carboxymethyl,
aminocarbonylmethyl, 1-(N,N-dimethylamino)ethyl and the like being
preferred. Of these, alkyl groups having 1-5 carbon atoms, which
have been substituted by 1-3 hydroxyl groups, are particularly
preferred.
In the general formula (Ic), a hydrogen atom and hydrocarbon groups
having 1-20 carbon atoms, preferably 1-5 carbon atoms, which may be
substituted by 1-5 hydroxyl groups, are preferred as R.sup.34,
R.sup.35, R.sup.36, R.sup.37 and R.sup.38. Of these, are
particularly preferred a hydrogen atom; alkyl groups having 1-20
carbon atoms, such as methyl, ethyl, butyl, hexyl, tetradecyl and
octadecyl; aryl groups such as phenyl; aralkyl groups such as
benzyl; and alkyl groups substituted by 1-5 hydroxyl groups, such
as hydroxymethyl, 2-hydroxyethyl, 1,2-dihydroxypropyl,
1,2,3-trihydroxybutyl, 1,2,3,4-tetrahydroxypentyl and
1,2,3,4,5-pentahydroxyhexyl.
In the general formula (Ic), compounds in which R.sup.33 is an
alkyl group having 1-3 carbon atom or an alkyl group having 1-5
carbon atoms, which has been substituted by 1-3 hydroxyl groups,
R.sup.34 is a hydrogen atom, or a 2-hydroxyethyl, methyl or benzyl
group, and R.sup.35, R.sup.36, R.sup.37 and R.sup.38 are
individually a hydrogen atom, or a methyl, hydroxymethyl,
2-hydroxyethyl or 1,2,3,4-tetra-hydroxypentyl group are
particularly preferred. (IIa), (IIb): ##STR43## wherein R.sup.39
means a linear, branched or cyclic hydrocarbon group having 1-40
carbon atoms, which may contain a heteroatom, R.sup.40 and R.sup.41
are identical with or different from each other and denote
individually a divalent hydrocarbon group having 1-3 carbon atoms,
R.sup.42 represents a hydrogen atom or a hydrocarbon group having
1-3 carbon atoms, R.sup.43 stands for a hydrogen atom or a
hydrocarbon group having 1-3 carbon atoms or ##STR44## R.sup.44 is
a hydrogen atom or a hydrocarbon group having 1-10 carbon atoms,
which may have one or more hydroxyl groups, R.sup.45 and R.sup.46
are identical with or different from each other and represent
individually a hydrocarbon group having 1-3 carbon atoms, which may
have 1-3 hydroxyl groups, and Y.sup.1 means a hydrocarbon group
having 1-10 carbon atoms and containing one or more groups selected
from the group consisting of a hydroxyl group, alkoxyl group,
hydroxyalkyloxy group, phosphoric acid residue, carboxyl group and
alkoxycarbonyl group, with the proviso that in the formula (IIa),
the case where both R.sup.40 and R.sup.41 are --CH.sub.2 --, both
R.sup.42 and .sup.43 are hydrogen atoms, and Y.sup.1 is the
following formula (a): ##STR45## in which R.sup.47, R.sup.48,
R.sup.49 and R.sup.50 have the same meaning as R.sup.44, is
excluded.
In the general formula (IIa) or (IIb), the hydrocarbon group
represented by R.sup.39 may be either saturated or unsaturated.
Such a group is preferably a linear, branched or cyclic hydrocarbon
group having 1-25 carbon atoms, more preferably a linear or
branched hydrocarbon group having 1-25 carbon atom, further
preferably a linear or branched hydrocarbon group having 1-3 or
14-22 carbon atoms, particularly preferable a linear or branched
alkyl or alkenyl group having 1-3 or 14-22 carbon atoms.
Examples of the heteroatom contained in R.sup.39 include oxygen,
nitrogen, silicon and sulfur atoms. Of these, an oxygen atom and/or
a nitrogen atom is preferred, with an oxygen atom being
particularly preferred. The heteroatom in R.sup.39 is contained in
the form of an atomic group containing at least one heteroatom.
Example of such an atomic group include hydroxyl, alkoxyl,
alkoxycarbonyl, alkanoyl, alkanoylamino, amino, mono-, di- or
tri-alkylamino, trialkylsilyl and alkylidenedioxy groups. The
numbers of carbon atoms in the alkyl and alkanoyl groups included
in such atomic groups are preferably 1-6.
Particularly preferable specific examples of R.sup.39 include
groups such as methyl, ethyl, propyl, butyl, hexyl, heptyl, octyl,
decyl, dodecyl, tetradecyl, pentadecyl, hexadecyl, octadecyl,
docosyl, dotriacontyl, methyl-branched isostearyl, 2-ethylhexyl,
2-heptylundecyl, 5,7,7-trimethyl-2-(1,3,3-trimethylbutyl)octyl,
9-octadecenyl, 9,12-octadecadienyl, cyclohexyl, phenyl, benzyl,
cholesteryl, 12-hydroxyoctadecyl, 12-hydroxydodecyl,
9-hydroxynonyl, 9,10-dihydroxyoctadecyl, 12-hydroxy-9-octadecenyl,
12-methoxyoctadecyl, 10-(2-ethylhexyloxy)decyl, 11-carboxyundecyl,
11-butoxycarbonylundecyl, 11-(2-ethylhexanoylamino)undecyl,
11-(butyldimethylsilyl)undecyl, tocopheryl and
9,10-isopropylidenedioxyoctadecyl. Of these, methyl,
methyl-branched isostearyl and 12-hydroxyoctadecyl are particularly
preferred.
R.sup.40 and R.sup.41 are preferably alkylene or alkylidene groups
having 1-3 carbon atoms. Specific examples thereof include
methylene, ethylene, trimethylene, propylene, ethylidene and
isopropylidene.
R.sup.42 is preferably a hydrogen atom or an alkyl group having 1-3
carbon atoms. Specific examples thereof include a hydrogen atom,
methyl, ethyl, n-propyl and isopropyl.
Examples of the hydrocarbon group of R.sup.43 include alkyl or
alkenyl groups having 1-3 carbon atoms. Preferable specific
examples thereof include methyl, ethyl, n-propyl, isopropyl, vinyl
and allyl groups. The group ##STR46## which may be indicated by
R.sup.43, may form a salt with sodium, potassium or the like Of
these groups indicative of R.sup.43, a hydrogen atom and methyl
group are particularly preferred.
As the hydrocarbon groups represented by R.sup.44, R.sup.47,
R.sup.48, R.sup.49 and R.sup.50, are preferred alkyl, alkenyl, aryl
or aralkyl groups having 1-10 carbon atoms, which may have one or
more hydroxyl groups. Further preferable examples thereof include
alkyl groups having 1-6 carbon atoms, such as methyl, ethyl,
propyl, butyl, pentyl and hexyl groups; phenyl group, benzyl group,
and alkyl groups having 1-6 carbon atoms, which have been
substituted by 1-6 hydroxyl groups, such as 2-hydroxyethyl,
2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl,
2,3,4,5-tetrahydroxypentyl and 2,3,4,5,6-pentahydroxyhexyl
groups.
Examples of the hydrocarbon groups represented by R.sup.45 and
R.sup.46, which may have 1-3 hydroxyl groups, include alkyl and
alkenyl groups having 1-3 carbon atoms, and groups derived from
these groups, which have been substituted by 1-3 hydroxyl groups.
Specific examples thereof include methyl, ethyl, n-propyl,
isopropyl, allyl, hydroxymethyl and 2-hydroxyethyl groups. Of these
groups indicative of R.sup.45 and R.sup.46, methyl, ethyl, n-propyl
and 2-hydroxyethyl groups are preferred, with a methyl group being
particularly preferred.
Examples of the hydrocarbon groups represented by Y.sup.1 and
having 1-10 carbon atoms include alkyl, alkenyl, aryl or aralkyl
groups having 1-10 carbon atoms. Examples of alkoxyl,
hydroxyalkyloxy and alkoxycarbonyl groups which are substitutable
on these hydrocarbon groups include alkoxyl group having 1-6 carbon
atoms; hydroxyalkyloxy groups having 1-4 carbon atoms; and
alkoxycarbonyl groups having 2-7 carbon atoms, respectively.
In some cases, Y.sup.1 may be a group represented by the following
formula (a): ##STR47## in which R.sup.47, R.sup.48, R.sup.49 and
R.sup.50 have the same meaning as defined above. In the formula
(IIa), the case where Y.sup.1 is such a group, both R.sup.40 and
R.sup.41 are methylene, and both R.sup.42 and .sup.43 are hydrogen
atoms is excluded. In the formula (a), R.sup.47 and R.sup.48 are
preferably individually a hydrogen atom, or a hydroxymethyl,
methyl, ethyl or 2-hydroxyethyl group, with a hydrogen atom, or a
methyl or hydroxymethyl group being particularly preferred.
Besides, R.sup.49 and R.sup.50 are preferably individually a
hydrogen atom, or a hydroxymethyl or 1,2,3,4-tetrahydroxybutyl
group, with a hydrogen atom being particularly preferred.
Preferable specific examples of Y.sup.1 include groups such as
--(CH.sub.2).sub.2 OH, --(CH.sub.2).sub.3 --OH, --(CH.sub.2).sub.6
OH, ##STR48##
The amine derivatives (IIb) have a quaternary ammonium structure.
Examples of counter ions thereof include inorganic ions such as
chlorine, sulfuric acid, nitric acid and phosphoric acid, and ions
of organic acids such as succinic acid, fumaric acid, lactic acid,
glycolic acid, citric acid, tartaric acid and benzoic acid.
In each of the general formulae (IIa) and (IIb), compounds in which
Y.sup.1 is a group represented by the formula (a) are preferred. Of
these, those in which R.sup.39 is a linear, branched or cyclic
hydrocarbon group having 1-25 carbon atoms, which may contain a
heteroatom, R.sup.43 is a hydrogen atom or a hydrocarbon group
having 1-3 carbon atom, R.sup.44 or R.sup.45 and R.sup.46 are
individually a hydrocarbon group having 1-3 carbon atoms, which may
have at least one hydroxyl group, and R.sup.47, R.sup.48, R.sup.49
and R.sup.50 are individually a hydrogen atom or a hydrocarbon
group having 1-10 carbon atoms, which may have one or more hydroxyl
groups are preferred.
Those in which R.sup.39 is a linear or branched hydrocarbon group
having 1-22 carbon atoms, which may contain an oxygen atom,
R.sup.43 is a hydrogen atom or a methyl group, R.sup.44 or R.sup.45
and R.sup.46 are individually a hydrocarbon group having 1-3 carbon
atoms, R.sup.47 and R.sup.48 are individually a hydrogen atom or a
methyl or hydroxymethyl group, and R.sup.49 and R.sup.50 are
individually a hydrogen atom are further preferred.
Those in which R.sup.39 is a 12-hydroxyoctadecyl group, R.sup.43 is
a hydrogen atom, R.sup.44 or R.sup.45 and R.sup.46 are individually
a hydrocarbon group having 1-3 carbon atoms, R.sup.47 and R.sup.48
are individually a hydrogen atom or a methyl or hydroxymethyl
group, and R.sup.49 and R.sup.50 are individually a hydrogen atom
are further preferred. (IIc): ##STR49## wherein R.sup.51 means a
hydrogen atom or a linear, branched or cyclic hydrocarbon group
having 1-40 carbon atoms, R.sup.52 denotes a hydrogen atom or a
hydrocarbon group having 1-5 carbon atoms, which may have one or
more hydroxyl groups, R.sup.53 stands for a hydrogen atom or a
hydrocarbon group having 1-22 carbon atoms, which may have one or
more hydroxyl or alkoxyl groups, R.sup.54 represents a hydrogen
atom or a hydrocarbon group having 1-7 carbon atoms, which may have
one or more hydroxyl groups, R.sup.55 means a hydrogen atom or a
hydrocarbon group having 2-6 carbon atoms, which may have one or
more hydroxyl groups, X.sup.1 denotes a hydrogen atom, hydroxyl
group or ##STR50## and Y.sup.2 represents a hydrogen atom or
##STR51##
In the formula (IIc), the hydrocarbon group represented by R.sup.51
may be either saturated or unsaturated. Preferable specific
examples thereof include groups such as methyl, ethyl, propyl,
butyl, hexyl, octyl, decyl, dodecyl, tetradecyl, hexadecyl,
eicosyl, methyl-branched isopalmityl, 7-hexadecenyl,
4,8,12-trimethyltridecyl, 4-methyl-3-pentenyl, cyclohexyl and
phenyl.
Preferable examples of the hydrocarbon group represented by
R.sup.52 include groups such as methyl, ethyl, butyl, pentyl,
hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl and
5-hydroxypentyl.
Preferable examples of the hydrocarbon group represented by
R.sup.53 include groups such as methyl, ethyl, butyl, hexyl,
phenyl, benzyl, hydroxymethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl,
1,2,3-trihydroxypropyl, 1,2,3,4-tetrahydroxybutyl,
1,2,3,4,5-pentahydroxypentyl, methoxymethyl, dodecyloxymethyl,
tetradecyloxymethyl and methyl-branched isostearyloxy.
Preferable examples of the hydrocarbon group represented by
R.sup.54 include groups such as methyl, ethyl, butyl, hexyl,
phenyl, benzyl, hydroxymethyl, 2,3-dihydroxypropyl,
2,3,4-trihydroxybutyl, 2,3,4,5-tetrahydroxypentyl and
2,3,4,5,6-pentahydroxyhexyl. Preferable groups as R.sup.55 include
--(CH.sub.2).sub.2 --, --(CH.sub.2).sub.3 --, --(CH.sub.2).sub.4
--, --(CH.sub.2).sup.5 --, --(CH.sub.2).sub.6 --, ##STR52## and the
like.
In the general formula (IIc), the phosphoric acid residue, which
may be indicated by X.sup.1 and Y.sup.2, may form a salt with a
metal or amine. (lid): ##STR53## wherein R.sup.56 means a linear or
branched hydrocarbon group having 8-40 carbon atoms, which may have
a hydroxyl group, R.sup.57, R.sup.58 and R.sup.59 are identical
with or different from each other and denote individually denotes a
hydrogen atom or a hydrocarbon group having 1-7 carbon atoms, which
may have one or more hydroxyl groups, R.sup.60 stands for a
hydrocarbon group having 2-6 carbon atoms, which may have one or
more hydroxyl or alkoxyl groups, X.sup.2 is --OR.sup.61, --CO.sub.2
R.sup.62 or ##STR54## (R.sup.61, R.sup.62, R.sup.63 and R.sup.64
are identical with or different from one another and denote
individually a hydrogen atom or a hydrocarbon group having 1-20
carbon atoms, which may contain an oxygen atom), and Y.sup.3
represents a hydrogen atom or a hydroxyl group.
In the general formula (IId), the divalent hydrocarbon group
indicated by R.sup.56 may be either saturated or unsaturated.
Specific examples thereof include groups such as octamethylene,
nonamethylene, decamethylene, undecamethylene, dodecamethylene,
tridecamethylene, tetradecamethylene, hexadecamethylene,
triacontamethylene, hexadecane-1,10-diyl, 7-hexadecene-1,10-diyl,
2-hydroxyundecane-1,11-diyl, 2-hydroxytridecane-1,13-diyl and
2-hydroxytetradecane-1,14-diyl.
Preferable examples of R.sup.57, R.sup.58 and R.sup.59 include a
hydrogen atom and groups such as methyl, ethyl, butyl, hexyl,
phenyl, benzyl, hydroxymethyl, hydroxyethyl, 1,2-dihydroxyethyl,
1,2,3-trihydroxypropyl, 1,2,3,4-tetrahydroxybutyl and
1,2,3,4,5-pentahydroxypentyl.
Preferable groups as R.sup.60 include --(CH.sub.2).sub.2 --,
--(CH.sub.2).sub.3 --, --(CH.sub.2).sub.4 --, --(CH.sub.2).sub.5
--, --(CH.sub.2).sub.6 --, ##STR55## and the like.
In the general formula (IId), the hydrocarbon groups having 1-20
carbon atoms represented by R.sup.61, R.sup.62, R.sup.63 and
R.sup.64, which may contain an oxygen atom, may be any of linear,
branched and cyclic hydrocarbon groups. Preferable specific
examples thereof include a hydrogen atom, and groups such as
methyl, ethyl, butyl, hexyl, octyl, dodecyl, hexadecyl, octadecyl,
2-ethylhexyl, allyl, 2-hydroxyethyl, 2,3-dihydroxypropyl,
2-hydroxypropyl, 6-hydroxyhexyl, 9-hydroxynonyl, 12-hydroxydodecyl,
phenyl, benzyl and tetrahydropyranyl.
In the general formula (IId), amine derivatives (IId') in which
R.sup.56 is a linear or branched hydrocarbon group having 8-40
carbon atoms, and Y.sup.3 is a hydroxyl group, and amine
derivatives (IId") in which R.sup.56 is an undecamethylene,
dodecamethylene, tridecamethylene or tetradecamethylene group,
X.sup.2 is a hydroxyl group, and Y.sup.3 is a hydrogen atom are
novel compounds. Therefore, the present invention also provides
such compounds or acid-added salts thereof. (IIe): ##STR56##
wherein R.sup.65 means a linear, branched or cyclic hydrocarbon
group having 1-40 carbon atoms, which may contain a heteroatom,
R.sup.66 and R.sup.68 are identical with or different from each
other and denote individually a hydrogen atom or a hydrocarbon
group having 1-10 carbon atoms, which may have a hydroxyl group,
R.sup.67 stands for a hydrocarbon group having 2-10 carbon atoms,
which may be substituted by a hydroxyl group, and A represents
--CO.sub.2 --,--S-- or ##STR57##
The heteroatom contained in R.sup.1 of the amine derivatives
represented by the general formula (IIe) is preferable O, S, N, Si
or the like.
In the general formula (IIe), R.sup.65 is a saturated or
unsaturated hydrocarbon. Specific example thereof include groups
such as methyl, ethyl, propyl, butyl, hexyl, octyl, decyl, dodecyl,
tetradecyl, pentadecyl, hexadecyl, octadecyl, docosyl,
dotriacontyl, methyl-branched isostearyl, 2-ethylhexyl,
2-heptylundecyl, 5,7,7-trimethyl-2-(1,3,3-trimethylbutyl)octyl,
9-octadecenyl, 9,12-octadecadienyl, cyclohexyl, phenyl, benzyl,
cholesteryl, 12-hydroxyoctadecyl, 12-hydroxydodecyl,
9-hydroxynonyl, 9,10-dihydroxyoctadecyl, 12-hydroxy-9-octadecenyl,
12-methoxy-octadecyl, 10-(2-ethylhexyloxy)decyl, 11-carboxyundecyl,
11-butoxycarbonylundecyl, 11-(2-ethylhexanoylamino)undecyl,
11-(butyldimethylsilyl)undecyl, tocopheryl and
9,10-isopropylidenedioxyoctadecyl.
In the general formula (IIe), as R.sup.66 and R.sup.68 are
preferred a hydrogen atom, and groups such as methyl, ethyl, butyl,
hexyl, phenyl, benzyl, 2-hydroxyethyl, 2,3-dihydroxypropyl,
2,3,4-trihydroxybutyl, 2,3,4,5-tetrahydroxypentyl and
2,3,4,5,6-pentahydroxyhexyl.
Preferable examples of the hydrocarbon group represented by
R.sup.67 include --(CH.sub.2).sub.2 --, --(CH.sub.2).sub.3 --,
--(CH.sub.2).sub.4 --, --(CH.sub.2).sub.5 --, --(CH.sub.2).sub.6
--, ##STR58##
In the general formula (lIe), those (IIe') in which R.sup.65 is a
linear or branched hydrocarbon group having 7-24 carbon atoms and
containing an oxygen atom are novel compounds. Therefore, the
present invention also provides such compounds or acid-added salts
thereof. Specific examples of such R.sup.65 include groups such as
12-hydroxy-octadecyl, 12-hydroxydodecyl, 9-hydroxynonyl,
9,10-dihydroxyoctadecyl, 12-hydroxy-9-octadecenyl,
12-methoxyoctadecyl, 10-(2-ethylhexyloxy)decyl, 11-carboxyundecyl,
11-butoxycarbonylundecyl and 11-(2-ethylhexanoylamino)undecyl.
(IIf): ##STR59## wherein R.sup.69 means a linear, branched or
cyclic hydrocarbon group having 1-40 carbon atoms, which may
contain a heteroatom, R.sup.70 and R.sup.71 are identical with or
different from each other and denote individually a hydrogen atom
or a hydrocarbon group having 1-10 carbon atoms, which may have one
or more hydroxyl groups, R.sup.72 represents a hydrocarbon group
having 2-6 carbon atoms, which may have one or more hydroxyl
groups, and m stands for an integer of 2-6.
Examples of the heteroatom contained in R.sup.69 of the amine
derivatives represented by the general formula (IIf) include
oxygen, sulfur, nitrogen and silicon atoms, with an oxygen atom
being particularly preferred.
In the general formula (IIf), R.sup.69 is a saturated or
unsaturated hydrocarbon group. Preferable specific examples thereof
include groups such as methyl, ethyl, propyl, pentyl, heptyl,
nonyl, undecyl, tridecyl, pentadecyl, heptadecyl, hentriacontyl,
methyl-branched isoheptadecyl, hepta-3-yl, heptadeca-8-yl,
8-heptadecenyl, 8,11-heptadecadienyl, 9-decenyl, cyclohexyl,
phenyl, 8-hydroxyoctyl, 11-hydroxyundecyl, 14-hydroxytetradecyl,
15-hydroxypentadecyl, 11-hydroxyheptadecyl,
8,9-dihydroxyheptadecyl, 11-hydroxy-8-heptadecenyl,
11-methoxyheptadecyl, 9-(2-ethylhexyl)nonyl, 10-carboxydecyl,
10-butoxycarbonyldecyl, 10-(2-ethylhexanoylamino)decyl,
10-(butyldimethylsilyl)decyl and
8,9-isopropylidenedioxyheptadecyl.
As R.sup.70 and R.sup.71, are preferred a hydrogen atom, and groups
such as methyl, ethyl, butyl, hexyl, phenyl, benzyl,
2-hydroxyethyl, 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl,
2,3,4,5-tetrahydroxypentyl and 2,3,4,5,6-pentahydroxyhexyl.
In the general formula (IIf), preferable groups as R.sup.67 include
--(CH.sub.2).sub.2 --, --(CH.sub.2).sub.3 --, --(CH.sub.2).sub.4
--, --(CH.sub.2).sub.5 --, --(CH.sub.2).sub.6 --, ##STR60## and the
like.
In the general formula (IIf), m is particularly preferably 2 or
3.
Of these compounds represented by the general formula (IIf), those
in which R.sup.69 is a linear or branched hydrocarbon group having
7-24 carbon atoms and containing an oxygen atom are particularly
preferred. (IIg): ##STR61## wherein R.sup.73 means a linear,
branched or cyclic hydrocarbon group having 1-40 carbon atoms,
which may have a hydroxyl group, ##STR62##
In the general formula (IIg), the hydrocarbon group indicated by
R.sup.73 may be either saturated or unsaturated. Preferable
specific examples thereof include groups such as 1-pentadecenyl,
pentadecyl, 1-hydroxypentadecyl, 1-heptadecenyl, heptadecyl,
1-hydroxyheptadecyl, methyl, ethyl, 1-nonenyl, 1-undecenyl,
1-tridecenyl, 1-nonadecenyl, 11-hydroxyheptadecenyl,
13-hydroxynonadecenyl, 9-methylhexadecyl and
11-methyloctadecenyl.
Four stereoisomers (D-erythro form, D-threo form, L-erythro form
and L-threo form) exist in the amine derivatives represented by the
general formula (IIg). In the present invention, any of them may be
used, or they may be used in any combination thereof.
Of these amine derivatives (IIg), the naturally occurred products
are obtained by extracting phospholipid, ceramide or the like,
which contains them, from an appropriate tissue (for example,
bovine brain), hydrolyzing it and then extracting them with an
organic solvent.
Sphingosine analogues (IIg) can be synthesized in accordance with a
process described in J. Am. Chem. Soc., Vol. 95, 4098 (1973); J.
Lipid Res., Vol. 19, 250 (1978); Tetrahedron Lett., Vol. 29, 239
(1988); Tetrahedron, Vol. 42, 5961 (1986); or the like. The
N-methyl-substituted products, N,N-dimethyl-substituted products
and N,N,N-trimethyl-substituted products thereof can be synthesized
by subjecting these sphingosine analogues to N-methylation in
accordance with a process described in Biochemistry, Vol. 7, 2192
(1968) or the like. (IIh): ##STR63## wherein R.sup.74 and R.sup.75
mean individually a hydrogen atom or a hydrocarbon group having
1-40 carbon atoms, which may have a hydroxyl, carboxyl, alkoxyl,
alkylthio, acylamino or acyloxy group, R.sup.76 denotes a hydrogen
atom or a hydrocarbon group having 1-40 carbon atoms, which may
have an alkoxyl, alkylthio, acylamino or acyloxy group, or a
hydrocarbon group having 1-40 carbon atoms, which may have a
hydroxyl or carboxyl group, with the proviso that the total number
of carbon atoms contained in R.sup.74, R.sup.75 and R.sup.76 is at
least 5, and R.sup.77 and R.sup.78 stand individually for a
hydrogen atom, a hydrocarbon group having 1-10 carbon atoms or a
nitrogen atom, or may form a heterocyclic ring, which may contain
an oxygen atom, together with the adjacent nitrogen atom.
In the general formula (IIh), preferable examples of R.sup.74 and
R.sup.75 include a hydrogen atom, and groups such as methyl, ethyl,
decyl, dodecyl, tetradecyl, hexadecyl, cyclohexyl, phenyl,
hydroxymethyl, 1-hydroxydodecyl, 1-hydroxytetradecyl,
1-hydroxyhexadecyl, 9-hydroxynonyl, 13-hydroxytridecyl,
14-hydroxytetradecyl, carboxy, 8-carboxyoctyl, 12-carboxydodecyl,
13-carboxytridecyl, dodecyloxymethyl, tetradecyloxymethyl,
hexadecyloxymethyl, methyl-branched isostearyloxymethyl,
12-hydroxyoctadecyloxymethyl, 15-hydroxypentadecyloxymethyl,
9-(2-ethylhexyloxy)nonyloxymethyl, dodecylthiomethyl,
tetradecylthiomethyl, dodecanoylaminomethyl,
tetradecanoylaminomethyl, hexadecanoylaminomethyl, methyl-branched
isostearoylaminomethyl, 12-hydroxyoctadecanoylaminomethyl,
15-hydroxypentadecanoylaminomethyl,
16-hydroxyhexadecanoylaminomethyl,
12-(2-ethylhexyloxy)dodecanoylaminomethyl,
11-(2-ethylhexanoylamino)undecanoylaminomethyl,
dodecanoyloxymethyl, tetradecanoyloxymethyl, methyl-branched
isostearoyloxymethyl and 2-ethylhexyloxymethyl.
Of the specific examples mentioned as R.sup.74 and R.sup.75, those
other than hydroxymethyl and carboxyl groups are preferred as
R.sup.76 The total number of carbon atoms contained in R.sup.74,
R.sup.75 and R.sup.76 is preferably at least 5.
Preferable examples of R.sup.77 and R.sup.78 include a hydrogen
atom, groups such as methyl, ethyl, propyl, hexyl, cyclohexyl,
phenyl and benzyl, and the following groups formed together by
R.sup.77 and R.sup.78 : ##STR64##
These amine derivatives (I) or (II) may be converted into
acid-added salts by reacting an amine derivative (I) or (II) with
an acid in accordance with the method known per se in the art. More
specifically, they may be converted into salts with an inorganic
acid such as hydrochloric acid, sulfuric acid, nitric acid or
phosphoric acid, or salt with an organic acid such as succinic
acid, fumaric acid, hexadecanoic acid, octadecanoic acid, lactic
acid, glycolic acid, citric acid, tartaric acid or benzoic acid.
They may also be converted into quaternized products by reacting
them with a lower alkyl halide.
Since the amine derivative (I) or (II), or an acid-added salt or
quaternized product thereof has an effect of preventing the
occurrence of wrinkles and smoothing or removing the wrinkles, this
can be applied to the skin, thereby smoothing or removing wrinkles,
and so it can be used as an agent for preventing or smoothing
wrinkles.
Such an agent for wrinkles may be administered in any way, for
example, internal use, external application or the like. As other
effective ingredients, antiphlogistics, vitamins and the like,
which are routinely used, may be suitably incorporated in addition
to the amine derivative (I) or (II), or the acid-added salt or
quaternized product thereof as needed.
On the other hand, the amine derivative (I) or (II), or the
acid-added salt or quaternized product thereof has effects of
inhibiting the synthesis of epidermic cell DNA, facilitating
embryonic induction and inhibiting epidermis hypertrophy. Namely,
since it has an effect of normalizing the abnormal keratinization
of epidermis cells, it can be applied to the skin, thereby
improving keratinization. Therefore, it can be used as a
keratinization-improving agent.
The amine derivative (I) or (II), or the acid-added salt or
quaternized product thereof also has an effect (beautifying effect)
of facilitating the keratinization of the skin and hence has an
effect of accelerating the metabolism of melanin which is a
causative substance of pigmentation in the skin caused by sunburn
or the like, thereby improving the pigmentation in the skin. It can
thus be used as a beautifier.
As with the agent for preventing or smoothing wrinkles, the
keratinization-improving agent and beautifier may be administered
in any way, for example, internal use, external application or the
like. As other effective ingredients, antiphlogistics, vitamins and
the like, which are routinely used, may be suitably incorporated in
addition to the amine derivative (I) or (II), or the acid-added
salt or quaternized product thereof as needed.
The amine derivative (I) or (II), or the acid-added salt or
quaternized product thereof is incorporated as an effective
ingredient into a dermatologic preparation (external skin care
preparation). The dermatologic preparation may be used in various
forms such as medicinal dermatologic preparations, cosmetic
dermatologic preparations and cosmetic compositions.
Examples of the medicinal and cosmetic dermatologic preparations
include various ointments containing one or more
medicinally-effective ingredients.
Ointments include both those containing an oily base as a base and
those containing an oil/water or water/oil emulsion-type base as a
base. No particular limitation is imposed on the oily bases. For
example, plant oils, animal oils, synthetic oils, fatty acids,
natural and synthetic glycerides, etc. may be mentioned. No
particular limitation is imposed on the medicinally-effective
ingredients. For example, one or more of analgesic and
antiphlogistic agents, analgesics, disinfectants, astringents,
emollients, hormones, vitamins and the like may be used suitably as
needed.
When used as a cosmetic composition, it is possible to incorporate
those ingredients employed routinely as cosmetic ingredients such
as oily substances, moisturizers, ultraviolet absorbents,
beautifiers, alcohols, chelating agents, pH adjustors, antiseptics,
thickeners, coloring matters, perfume bases, vegetable extracts and
the like in combination as needed.
As cosmetics, cosmetic compositions of various forms and uses may
be formulated including, for example, oil/water or water/oil type
emulsified cosmetics, creams, cosmetic emulsions, toilet waters,
oily cosmetics, lip sticks, foundations, skin cleansing
compositions, hair tonics, hair styling compositions, hair grooming
compositions, hair growth stimulants and bath additive
compositions. The dermatologic preparations according to the
present invention may be formulated into the above various forms by
the conventional methods.
No particular limitation is imposed on the proportion of the amine
derivative (I) or (II), or the acid-added salt or quaternized
product thereof in the dermatologic preparations. In the case of
the emulsion-type dermatologic preparation, however, its proportion
may preferably be 0.0001-5 wt. % (hereinafter indicated merely by
"%"), more preferably 0.0001-1%, particularly 0.0001-0.1% of the
total weight of the composition. In the case of the oil-based
dermatologic preparation containing a liquid hydrocarbon such as
squalane on the other hand, its proportion may preferably be
0.0001-10%, more preferably 0.0001-1%, particularly 0.0001-0.1% of
the total weight of the composition.
EXAMPLES
The present invention will hereinafter be described further by the
following examples.
Example 1
Preparation of
1-(2-hydroxyethylamino)-3-(12-hydroxyoctadecyloxy)-2-propanol
(1a-1): ##STR65## (1) Preparation of 1,12-octadecanediol:
A 5-liter flask equipped with a stirrer, dropping funnel and reflux
tube was charged with 28.5 g (0.75 mol) of LiAlH.sub.4 and 2 liters
of tetrahydrofuran, to which a solution of 237.0 g (0.75 mol) of
methyl 12-hydroxyoctadecanate in 1 liter of tetrahydrofuran was
added dropwise over 5 hours with stirring. After completion of the
dropping, the stirring was continued further for 1 hour at
65.degree. C. After the reaction mixture was then cooled, 90 ml of
a 5% aqueous solution of KOH were added with stirring. A salt
precipitated was separated by filtration, and the resultant
solution was concentrated under reduced pressure. The resulting
residue was purified by column chromatography on silica gel,
thereby obtaining 185.7 g (yield: 86.6%) of
1,12-octadecanediol.
(2) Preparation of 12-hydroxyoctadecyl glycidyl ether:
A 1-liter flask equipped with a stirrer, dropping funnel and reflux
tube was charged with 100 g (0.35 mol) of 1,12-octadecanediol
obtained above, 66.8 g (0.72 mol) of epichlorohydrin, 5.68 g (17.6
mmol) of tetrabutylammonium chloride, 50 ml of tetrahydrofuran and
50 ml of toluene. While stirring the mixture, 117 g (1.40 mol) of a
48% aqueous solution of NaOH were added dropwise over 1 hour at
50.degree. C. After stirring for 1 hour at 50.degree. C., the
mixture was added with 400 ml of water and subjected to extraction
with isopropyl alcohol. After the solvent was distilled off under
reduced pressure, the resultant residue was purified by column
chromatography on silica gel, thereby obtaining 47.0 g (yield: 45%)
of 12-hydroxyoctadecyl glycidyl ether.
(3) Preparation of
1-(2-hydroxyethylamino)-3-(12-hydroxyoctadecyloxy)-2-propanol
(Ia-1):
A 200-ml flask equipped with a stirrer, reflux condenser and
dropping funnel was charged with 35.0 g (0.57 mol) of ethanolamine
and 35 g of ethanol, and the mixture was heated to 80.degree. C.
with stirring in a nitrogen atmosphere. To this mixture, 13.0 g (38
mmol) of 12-hydroxyoctadecyl glycidyl ether were added dropwise
over 3 hours. After the resultant mixture was stirred further for 3
hours, it was concentrated under reduced pressure and purified by
column chromatography on silica gel, thereby obtaining 11.7 g
(yield: 77%) of the title compound (Ia-1).
Colorless powder.
Melting point: 71.8.degree.-72.5.degree. C.
IR (KBr, cm.sup.-1): 3298, 2920, 2848, 1470, 1341, 1122, 906,
852.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.88(t,J=6.43 Hz,3H),
1.10-1.70(m,30H), 2.52-3.15(m,8H), 3.30-3.54(m,7H),
3.82-4.00(m,1H).
Examples 2-4
Reactions were conducted in the same manner as in Example 1 except
that N-methylethanolamine, diethanolamine and
2-amino-2-methyl-1,3-propanediol were respectively used in place of
ethanolamine in the step (3) of Example 1, thereby preparing the
following amine derivatives (Ia-2)-(Ia-4). ##STR66## (Ia-2):
Colorless powder.
Melting point: 69.5.degree.-71.7.degree. C.
IR (NaCl, cm.sup.-1): 3304, 2924, 2852, 1464, 1346, 1124, 1032.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.81-0.96(m,3H), 1.13-1.67(m,
30H), 2.33(s,3H), 2.38-3.20(m,7H), 3.33-3.69(m,7H),
3.82-3.98(m,1H).
(Ia-3):
colorless wax.
Melting point: 40.6.degree.-43.6.degree. C.
IR (KBr, cm.sup.-1): 3340, 2924, 2852, 1468, 1116, 1074, 868.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.88(t,J=6.7 Hz, 3H),
1.03-1.82(m,30H), 2.32-2.87(m,6H) , 3.30-4.40(m,10H).
(Ia-4):
Colorless powder.
Melting point: 63.2.degree.-64.1.degree. C.
IR (NaCl, cm.sup.-1): 3320, 2912, 1458, 1380, 1118, 1046.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.82-0.97(m,3H), 1.10(s,3H),
1.18-1.67(m,30H), 2.72-3.06(m,2H), 3.41-3.79(m,9H),
3.79-4.92(br,6H).
Examples 5-7
Reactions were conducted in the same manner as in Examples 1 and 2
except that ethyl ricinolate was used in place of methyl
12-hydroxyoctadecanate in Examples 1 and 2, thereby preparing the
following amine derivatives (Ia-5)-(Ia-7). ##STR67## (Ia-5):
Yellow oil.
IR (NaCl, cm.sup.-1): 3372, 2924, 2856, 1454, 1370, 1116, 1056.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.75-1.02(m,3H),
1.08-1.70(m,22H), 1.90-2.30(m,4H), 2.48-2.84(m,4H), 3.08(brs,4H),
3.38-3.75(m,7H), 3.80-4.02(m,1H), 5.28-5.62(m,2H).
(Ia-6):
Pale yellow oil.
IR (NaCl, cm.sup.-1): 3404, 2924, 2856, 1456, 1362, 1120, 1080,
1034.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.81-0.96(m,3H) ,
1.12-1.67(m,22H), 1.96-2.13(m,2H), 2.21(t,J=6.6 Hz,2H), 2.34(s,3H),
2.37-2.77(m,7H), 3.32-3.53(m,4H), 3.53-3.62(m,3H), 3.82-3.97(m,1H),
5.30-5.63(m,2H).
(Ia-7):
Pale yellow oil.
IR (NaCl, cm.sup.-1): 3352, 2924, 2856, 1458, 1360, 1116, 1040.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.80-1.04(m,3H), 0.97(s,3H),
1.10-1.66(m,22H), 1.94-2.13(m,2H), 2.21(t,J=6.6 Hz,2H),
2.53-2.82(m,2H), 2.82-3.69(m,14H), 3.83-4.00(m,1H),
5.28-5.64(m,2H).
Example 8
A reaction was conducted in the same manner as in Example 1 except
that methyl 9,10-dihydroxyoctadecanate was used in place of methyl
12-hydroxyoctadecanate in Example 1, thereby preparing the
following amine derivative (Ia-8). ##STR68## (Ia-8):
Colorless powder.
Melting point: 108.9.degree.-109.8.degree. C.
IR (NaCl, cm.sup.-1): 3300, 2920, 2852, 1466, 1118, 1066.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.88(t,J=6.4 Hz,3H),
1.04-1.90(m,28H), 2.46-3.02(m,9H), 3.18-4.00(m,9H).
Examples 9-10
Reactions were conducted in the same manner as in Example 1 except
that 1,12-dodecanediol and 1,9-nonanediol were respectively used in
place of 1,12-octadecanediol in the step (2) of Example 1, thereby
preparing the following amine derivatives (Ia-9)-(Ia-10). ##STR69##
(Ia-9):
Colorless powder.
Melting point: 77.8.degree.-78.58.degree. C.
IR (NaCl, cm.sup.-1): 3396, 2916, 2852, 1464, 1116, 1050.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.00-1.88(m,20H),
2.05-2.88(m,8H), 3.10-4.05(m,9H).
(Ia-10):
Colorless powder.
Melting point: 68.6.degree.-70.8.degree. C.
IR (NaCl, cm.sup.-1): 3380, 3308, 2916, 2852, 1462, 1356, 1116,
1066, 954, 864, 720.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.13-1.77(m,14H),
2.56-2.90(m,4H), 3.30-3.99(m,9H).
Example 11
A reaction was conducted in the same manner as in Example 1 except
that methyl 9,10-epoxyoctadecanate was used in place of methyl
12-hydroxyoctadecanate in Example 1, thereby preparing the
following amine derivative (Ia-11). ##STR70## (Ia-11):
Colorless powder.
Melting point: 75.7.degree.-78-8.degree. C.
IR (NaCl, cm.sup.-1) : 3376, 2920, 2852, 1466, 1122, 1052.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.88(t,J=6.4 Hz,3H),
1.16-2.50(m,34H), 2.55-2.86(m,4H), 3.28-4.00(m,4H).
Example 12
Preparation of
1-(2-hydroxyethylamino)-3-(2-hydroxyoctadecyloxy)-2-propanol
(Ia-12): ##STR71## (1) Preparation of 2-hydroxyoctadecyl glycidyl
ether:
A 300-ml flask equipped with a stirrer and reflux tube was charged
with 58 g (1 mol) of allyl alcohol, to which 0.4 g (10 mmol) of 60%
NaH were added to completely dissolve it in the alcohol. Then, 26.9
g (0.1 mol) of 1,2-epoxyoctadecane were added to the solution. The
resultant mixture was heated and stirred for 6 hours at 100.degree.
C. After completion of the reaction, the reaction mixture was
neutralized with hydrochloric acid and subjected to extraction with
chloroform. After the solvent was distilled off under reduced
pressure, the resultant residue was purified by column
chromatography on silica gel, thereby obtaining 31.1 g (yield: 95%)
of 1-allyloxy-2-octadeoanol.
A flask equipped with a stirrer was then charged with 31.1 g (95
mmol) of 1-allyloxy-2-octadecanol obtained above, 25.9 g (0.15
mmol) of m-chloroperbenzoic acid and 100 ml of diohloromethane, and
the contents were stirred for 36 hours at room temperature. After
solids precipitated were separated by filtration, the solvent was
distilled off under reduced pressure, and the resultant residue was
purified by column chromatography on silica gel, thereby obtaining
24.9 g (yield: 76.5%) of 2-hydroxyoctadecyl glycidyl ether. (2)
Preparation of
1-(2-hydroxyethylamino)-3-(2-hydroxyoctadecyloxy)-2-propanol
(1-l):
A 300-ml flask equipped with a stirrer, reflux tube and dropping
funnel was charged with 40.5 g (0.66 mol) of ethanolamine and 8.6 g
of ethanol. While heating and stirring the mixture at 80.degree.
C., an ethanol solution of 4.08 g (11.8 mmol) of 2-hydroxyoctadecyl
glycidyl ether was added dropwise over 3 hours. After the resultant
mixture was heated and stirred further for 3 hours, it was poured
into 500 ml of ice water to collect crystals formed by filtration.
The thus-obtained crystals were recrystallized again from n-hexane,
thereby obtaining 3.58 g (yield: 75%) of the title compound
(Ia-12).
(Ia-12):
Colorless powder.
Melting point: 91.8.degree.-92.7.degree. C.
IR (NaCl, cm.sup.-1) : 3432, 2916, 2848, 1466, 1116, 1046.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.88(t,J=6.4 Hz,3H),
1.00-2.40(m,34H), 2.58-2.92(m,4H), 3.20-3.85(m,8H).
Example 13
A reaction was conducted in the same manner as in Example 1 except
that methyl 12-methoxyoctadecanate was used in place of methyl
12-hydroxyoctadecanate in Example 1, thereby preparing the
following amine derivative (Ia-13). ##STR72## (Ia-13):
Pale yellow oil.
IR (NaCl, cm.sup.-1) : 3312, 2928, 2856, 1458, 1372, 1100, 942,
856.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.78-1.00(m,3H),
1.08-1.70(m,30H), 2.50-2.88(m,6H), 2.75-3.52(m,9H),
3.56-3.78(m,2H), 3.80-4.00(m,1H).
Example 14
Preparation of
1-(2-hydroxyethylamino)-3-[10-(2-ethylhexyloxy)decyloxy]-2-propanol
(Ia-14): ##STR73## (1) Preparation of
10-(2-ethylhexyloxy)decanol:
A 1-liter flask equipped with a stirrer and distiller was charged
with 25 g (0.14 mol) of 1,10-decanediol, 8.09 g (0.14 mol) of KOH
and 300 ml of xylene, and the resultant mixture was heated at
120.degree. C. for 1 hour, thereby distilling off water formed. To
this reaction mixture, were added 23.1 g (0.12 mol) of 2-ethylhexyl
bromide, and the resulting mixture was heated and stirred for 15
hours. After completion of the reaction, the reaction mixture was
cooled to room temperature and washed with water. After the solvent
was distilled off under reduced pressure, the resulting residue was
purified by column chromatography on silica gel, thereby obtaining
24.8 g (yield: 72%) of 10-(2-ethylhexyloxy)decanol.
(2) Preparation of 10-(2-ethylhexyloxy)decyl glycidyl ether:
A 200-ml flask equipped with a stirrer, reflux tube and dropping
funnel was charged with 24.8 g (87 mmol) of
10-(2-ethylhexyloxy)decanol, 17.7 g (0.191 mol) of epichlorohydrin,
1.4 g (4.4 mmol) of tetrabutylammonium bromide and 25 ml of hexane.
While stirring the mixture at 40.degree. C., 29.2 g (0.35 mol) of a
48% aqueous solution of NaOH were added dropwise over 3 hours.
After completion of the dropping, the stirring was continued
further for 2 hours at 40.degree. C. After the resultant reaction
mixture was washed with water, and the solvent was distilled off
under reduced pressure, the resultant residue was purified by
column chromatography on silica gel, thereby obtaining 24.6 g
(yield: 82.6%) of 10-(2-ethylhexyloxy)decyl glycidyl ether.
(3) Synthesis of
1-(2-hydroxyethylamino)-3-[10-(2-ethylhexyloxy)decyloxy]-2-propanol
(Ia-14):
A 200-ml two-necked flask equipped with a stirrer, reflux tube and
dropping funnel was charged with 32.7 g (0.54 mol) of ethanolamine
and 10.1 g of ethanol. While heating and stirring the mixture at
80.degree. C., 1.76 g (5.14 mmol) of 10-(2-ethylhexyloxy)decyl
glycidyl ether were added dropwise over 2 hours. After the
resultant mixture was heated and stirred further for 18 hours, it
was concentrated under reduced pressure, and the resultant residue
was purified by column chromatography on silica gel, thereby
obtaining 1.42 g (yield: 68%) of the title compound (Ia-14).
(Ia-14):
Yellow oil.
IR (NaCl, cm.sup.-1) : 3400, 2924, 2856, 1464, 1114.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.75-1.05(m,6H),
1.10-2.17(m,25H), 2.50-3.12(m,7H), 3.14-4.15(m,11H).
Example 15
Preparation of butyl
12-[2-hydroxy-3-(2-hydroxyethylamino)propoxy]dodecanate (Ia-15):
##STR74## (1) Preparation of butyl
12-(2,3-epoxypropoxy)dodecanate:
A 500-ml flask equipped with a stirrer was charged with 10.8 g (50
mmol) of butyl 12-hydroxydodecanate, 18.2 g (150 mmol) of allyl
bromide, 6.0 g (150 mmol) of NaH and 100 ml of dimethylformamide,
and the resultant mixture was stirred for 24 hours at 50.degree.
C., to which 100 ml of butanol were further added, followed by
stirring at 50.degree. C. for 2 hours. The reaction mixture was
then added with water and subjected to extraction with isopropyl
alcohol, and the solvent was distilled off under reduced
pressure.
The thus-obtained residue was then charged into a 100-ml flask, and
10.2 g (50 mmol) of m-chloroperbenzoic acid and dichloromethane
were added thereto. The resultant mixture was stirred at room
temperature for 48 hours. After separating solids formed, the
solvent was distilled off under reduced pressure, and the resultant
residue was purified by column chromatography on silica gel,
thereby obtaining 8.67 g (yield: 52.8%) of butyl
12-(2,3-epoxypropoxy)dodecanate.
(2) Preparation of butyl
12-[2-hydroxy-3-(2-hydroxyethylamino)propoxy]dodecanate
(Ia-15):
A 100-ml flask equipped with a stirrer and dropping funnel was
charged with 23.7 g (250 mmol) of ethanolamine and 23.7 g of
ethanol. While stirring the mixture at 80.degree. C., an ethanol
solution of 8.20 g (25 mmol) of butyl
12-(2,3-epoxypropoxy)-dodecanate was added dropwise over 1 hour.
After completion of the reaction, water was added to the reaction
mixture, followed by extraction with chloroform. The resultant
chloroform solution was concentrated under reduced pressure, and
the resultant residue was purified by column chromatography on
silica gel, thereby obtaining 5.40 g (yield: 55.4%) of the title
compound (Ia-15).
(Ia-15):
Pale yellow solid.
Melting point: 48.6.degree.-50.2.degree. C.
IR (NaCl, cm.sup.-1) : 3452, 2940, 1728, 1466, 1326, 1116, 1050
862.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.93(t,J=7.2 Hz,3H),
1.21-1.87(m,22H), 2.29(t,J=7.4 Hz,2H), 2.42-3.03(m,7H),
3.34-3.61(m,4H), 3.62-3.80(m,2H), 3.82-4.00(m,1H), 4.07(t,J=6.6
Hz,2H).
Example 16
Preparation of
12-[2-hydroxy-3-(2-hydroxyethylamino)propoxy]dodecanoic acid
hydrochloride (Ia-16): ##STR75##
A 200 ml-flask equipped with a stirrer was charged with 3.90 (10
mmol) of the amine derivative (Ia-15) obtained in Example 15, 11 g
(0.1 mol) of a 50% aqueous solution of KOH and 100 ml of ethanol.
The mixture was stirred at 40.degree. C. for 2 hours. After
completion of the reaction, the reaction mixture was acidified with
hydrochloric acid, followed by extraction with chloroform. The
resultant chloroform solution was treated with active carbon and
then concentrated under reduced pressure, thereby obtaining 2.67 g
(yield: 72.2%) of the title compound (Ia-16).
(Ia-16):
Pale yellow wax.
IR (NaCl, cm.sup.-1) : 3264, 3032, 2924, 1724, 1628, 1458, 1116,
1066, 998, 746.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.17-1.70(m,18H), 2.27 (t,J=7.4
Hz,2H), 2.98-3.25(m,4H), 3.38-3.89(m,6H), 3.94-4.16(m,1H).
Example 17
Preparation of
N-[11-[2-hydroxy-3-(2-hydroxyethylamino)propoxy]undecyl]-2-ethylhexanamide
(Ia-17): ##STR76## (1) Preparation of
N-[11-(2,3-epoxypropoxy)undecyl]-2-ethylhexanamide:
A 200-ml flask equipped with a stirrer and dropping funnel was
charged with 9.37 g (50 mmol) of 11-aminoundecanol, 9.48 g (120
mmol) of pyridine and 50 ml of dichloromethane. While stirring the
mixture at room temperature, 8.13 g (50 mmol) of 2-ethylhexanoyl
chloride were added. After stirring at room temperature for 1 hour,
the mixture was added with water and subjected to extraction with
chloroform, and the resultant chloroform solution was concentrated
under reduced pressure.
The thus-obtained residue was then charged into a 200-ml flask
equipped with a stirrer, reflux tube and dropping funnel, and 13.9
g (150 mmol) of epichlorohydrin, 0.81 g (2.5 mmol) of
tetrabutylammonium bromide and 20 ml of hexane were added thereto.
While stirring the mixture at 40.degree. C., 20.8 g (250 mmol) of a
48% aqueous NaOH were added dropwise to the resultant mixture over
2 hours. After completion of the dropping, the resultant mixture
was stirred further for 48 hours at 40.degree. C., washed with
water and concentrated under reduced pressure. The resultant
residue was then purified by column chromatography on silica gel,
thereby obtaining 11.3 g (yield: 61.2%) of
N-[11-(2,3-epoxypropoxy)undecyl]-2-ethylhexanamide.
(2) Preparation of
N-[12-[2-hydroxy-3-(2-hydroxyethylamino)propoxy]undecyl]-2-ethylhexanamide
(Ia-17):
A 100-ml flask equipped with a stirrer, reflux tube and dropping
funnel was charged with 16.8 g (0.28 mol) of ethanolamine and 3.4 g
of ethanol. While heating and stirring the mixture at 80.degree.
C., an ethanol solution of 6.77 g (18.3 mmol) of
N-[12-(2,3-epoxypropoxy)undecyl]-2-ethylhexanamide was added
dropwise over 3 hours. After the heating and stirring were
conducted further for 30 minutes, the reaction mixture was
concentrated under reduced pressure, and the resultant residue was
purified by column chromatography on silica gel, thereby obtaining
6.47 g (yield: 82%) of the title compound (Ia-17).
(Ia-17):
Colorless solid.
Melting point: 76.1.degree.-77.3.degree. C.
IR (KBr, cm.sup.-1) : 3300, 3468, 2924, 2856, 1638, 1458, 1376,
1350, 1112, 1042.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.88(t,J=7.3 Hz,6H),
1.08-1.98(m,26H), 2.50-2.88(m,8H), 3.15-3.55(m,6H),
3.57-3.75(m,2H), 3.82-3.98(m,1H), 5.46-5.62(m,1H).
Example 18
Preparation of
1-(2-hydroxyethylamino)-3-[11-(butyldimethylsilyl)undecyloxy]-2-propanol
(Ia-18): ##STR77## (1) Synthesis of 11-(butyldimethylsilyl)undecyl
glycidyl ether:
A 100-ml flask equipped with a stirrer was charged with 13.6 g (60
mmol) of 10-undecenyl glycidyl ether, 5.8 g (50 mmol) of
butyldimethylsilane and 4 mg (0.01 mmol) of H.sub.2 PtCl.sub.6. The
contents were stirred at 60.degree. C. for 24 hours. The resultant
reaction mixture was distilled under reduced pressure
(145.degree.-154.degree. C./6.times.10.sup.-3 Torr), thereby
obtaining 14.15 g (yield: 82.6%) of 11-(butyldimethylsilyl)undecyl
glycidyl ether.
(2) Preparation of
1-(2-hydroxyethylamino)-3-[11-(butyldimethylsilyl)undecyloxy]-2-propanol
(Ia-18):
A 100-ml two-necked flask equipped with a stirrer, dropping funnel
and N.sub.2 inlet tube was charged with 4.58 g (75 mmol) of
ethanolamine and 9.2 g of ethanol. The contents were heated to
80.degree. C. with stirring in an N.sub.2 atmosphere, and an
ethanol solution of 1.71 g (5 mmol) of
11-(butyldimethylsilyl)undecyl glycidyl ether was added dropwise to
the contents over 1 hour. The resultant mixture was stirred further
for 1 hour at 80.degree. C. After completion of the reaction,
ethanol and excess ethanolamine were distilled off under reduced
pressure, and the resultant residue was purified by column
chromatography on silica gel, thereby obtaining 1.48 g (yield: 73%)
of the title compound (Ia-18).
(Ia-18):
Pale yellow oil.
IR (NaCl, cm.sup.-1) : 3348, 2924, 2856, 1462, 1248, 1116, 1052,
907, 826, 726.
.sup.1 H-NMR (CDCl.sub.3, .delta.): -0.13(s,6H), 0.37-0.45(m,4H),
0.81(t,J=6.6 Hz,3H), 1.05-1.62(m,22H), 2.50-2.78(m,4H),
3.23-4.08(m,10H).
Example 19
A reaction was conducted in the same manner as in Example 18 except
that 1,1,1,2,333-heptamethyltrisiloxane was used in place of
butyldimethylsilane in Example 18, thereby preparing the following
amine derivative (Ia-19). ##STR78##
Pale yellow oil.
IR (NaCl, cm.sup.-1) : 3312, 2924, 2852, 1448, 1348, 1252, 1046,
834.
.sup.1 H-NMR (CDCl.sub.3, .delta.): -0.06(s,3H), 0.03(s,18H),
0.33-0.46(m,2H), 1.06-1.62(m,14H), 2.51-2.79(m,4H),
3.25-3.96(m,10H).
Example 20
A reaction was conducted in the same manner as in Example 1 except
that 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl glycidyl ether
was used in place of 12-hydroxyoctadecyl glycidyl ether in the step
(3) of Example 1, thereby preparing the following amine derivative
(Ia-20). ##STR79##
Colorless amorphous.
IR (NaCl, cm.sup.-1) : 3316, 2908, 1449, 1194, 1143.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.42(tt,J=18.8 Hz,6.7 Hz,2H),
2.58-2.88(m,7H), 3.37-3.58(m,2H), 3.62-4.00(m,7H).
Example 21
Inhibitory effect of the amine derivatives on DNA synthesis of
epidermic keratinocyte:
(1) Method:
a) Culture of human epidermic keratinocyte:
Human normal keratinocytes (trade name: Epipack) commercially
available from Kurabo Industries Ltd. were purchased and used as
keratinocytes. Incidentally, a medium for human normal
keratinocytes (trade name: K-GM) commercially available from the
said firm was used in the maintenance and subculture of the
cells.
b) Determination of DNA synthesis (thymidine incorporation):
Keratinocytes cultured in a vegetative state in a 24-well plate
were used. A medium in each well was first removed by suction to
add 450 .mu.l of K-GM, to which no pituitary gland extract was
added, to the well, thereby making a medium exchange. Thereafter,
each of the amine derivatives (Ia-1) to (Ia-20) obtained in the
above synthesis examples was added thereto. Further, 0.2 .mu.Ci/ml
of [.sup.3 H] thymidine was subsequently added to incubate the
culture for 4 hours. After the supernatant was then removed by
suction, and the well was washed 3 times with PBS(-), 500 .mu.l of
2N NaOH were added. After the culture was incubated at 37.degree.
C. for 10 minutes, an equiamount of 2N HCl was added to neutralize
the culture, and 4 ml of 10% trichloroacetic acid chilled with ice
water were added, followed by leaving at rest for 30 minutes.
Precipitate was collected on a glass filter and then washed 3 times
with 3 ml of 10% trichloroacetic acid chilled with ice water. The
glass filter was washed further once with 3 ml of ethanol chilled
with ice water and then air-dried to measure its radioactivity by a
liquid scintillation counter, thereby calculating the thymidine
incorporation into the cells.
(2) Result:
The relative amounts of the [.sup.3 H] thymidine incorporated at
the time each of the amine derivatives (Ia-1) to (Ia-20) has been
added in amounts of 10 .mu.M and 100 .mu.M are shown in Table
1.
TABLE 1 ______________________________________ Relative amount of
[.sup.3 H] thymidine incorporated (%)* Amine derivative 10 .mu.M
100 .mu.M ______________________________________ (Ia-1) 21.8 8.2
(Ia-2) 17.3 4.4 (Ia-3) 47.9 15.5 (Ia-4) 25.5 8.3 (Ia-5) 16.4 4.2
(Ia-6) 9.4 1.0 (Ia-7) 31.0 13.0 (Ia-8) 28.3 7.9 (Ia-9) 70.3 32.0
(Ia-10) 75.3 30.9 (Ia-11) 18.7 4.2 (Ia-12) 19.3 2.1 (Ia-13) 11.8
1.1 (Ia-14) 16.1 4.2 (Ia-15) 59.3 17.0 (Ia-16) 98.7 13.7 (Ia-17)
11.0 0.9 (Ia-18) 14.3 1.8 (Ia-19) 51.7 21.4 (Ia-20) 80.2 33.5
______________________________________ *: Indicating the relative
value where a control is assumed to be 100%.
It was apparent from Table 1 that the thymidine incorporation is
markedly reduced by the addition of the amine derivatives, namely,
that the DNA synthesis of the human epidermic keratinocytes is
inhibited. Besides, the human epidermic keratinocytes treated under
the same conditions as described above were observed on the fourth
day. As a result, it was found that most of the cells turn
insoluble membrane (cornified envelope), i.e., become keratinized.
It is understood from this fact that the amine derivatives
according to the present invention are active in facilitating the
keratinization of epidermis.
Example 22
Effect of the amine derivatives on the transglutaminase activity of
epidermic keratinocyte:
(1) Determination of transglutaminase activity:
Keratinocytes cultured in a vegetative state in a 6-well plate were
used. A medium in each well was removed by suction to add 2 ml of
K-GM, to which no pituitary gland extract was added, to the well,
thereby making a medium exchange. Thereafter, each of the amine
derivatives (Ia-2) and (Ia-6) was added thereto. After 24 hours,
each well was washed 3 times with PBS(-), and the cells were then
separated and collected by a rubber policeman. The thus-obtained
cell suspension was centrifuged at 2,500 rpm for 10 minutes to
collect the sediment. To this sediment, were added 200 .mu.l of a
buffer (a) [10 mM Tris-HCl buffer, 10 mM DTT, 0.5 mM EDTA; pH 7.4],
followed by ultrasonication twice for 1 minute. The thus-obtained
suspension was centrifuged at 25,000 rpm for 30 minutes to obtain a
supernatant. This supernatant was divided into equiamount portions.
To each of the portions, was added a reaction solution [a solution
obtained by mixing 300 mM Tris-HCl buffer, pH 8.1; 100 .mu.l of 60
mM CaCl.sub.2 ; 100 .mu.l of 30 mM DTT; 100 .mu.l of distilled
water containing 540 .mu.g of dimethylcasein; 50 .mu.l of 12 mM
putrescine; 50 .mu.l of 2.5 .mu.Ci [.sup.14 C] putrescine; and 100
.mu.l of distilled water]. The thus-obtained mixture was incubated
at 37.degree. C. for 1 hour. After 600 .mu.l of 10% trichloroacetic
acid were then added to the mixture, and the resultant mixture was
left at rest for 30 minutes, precipitate was collected on a
nitrocellulose membrane of 0.45 .mu.m. After this membrane was
washed with 15 ml of 5% trichloroacetic acid (containing 1% of
putrescine) chilled with ice water, the radioactivity of the
precipitate on the membrane was determined by a liquid
scintillation counter.
(2) Result:
The values (dpm) of transglutaminase activities where each of the
amine derivatives (Ia-2) and (Ia-6) has been added in an amount of
10 .mu.M are shown in Table 2.
TABLE 2 ______________________________________ Transglutaminase
activity value (dpm) ______________________________________ Control
2752.8 Amine derivative 9520.1 (Ia-2) Amine derivative 13764.0
(Ia-6) ______________________________________
As apparent from the results shown in Table 2, the activity value
is increased by adding the amine derivative. Namely, it is
understood that the amine derivatives have an embryonic induction
activity against keratinocytes.
Example 23
Effect of the amine derivatives on wrinkles formed on hairless mice
by exposure to UVB:
(1) Hairless mice (HR/ICR, aged 9 weeks at the beginning of the
experiment) were each exposed to UVB 3 times a week by using 6
Toshiba healthy lamps, 20SE. The amount of energy was measured by
means of a UV-Radiometer UVR-305/365D manufactured by TOKYO OPTICAL
K.K. The dose upon one exposure was determined to be 1 MED or less,
i.e., 65 mj in an amount of energy of 0.28 mM/cm.sup.2. The
exposure was effected for 20 weeks. After confirming the fact that
the mice had got wrinkles at their backs, they were divided into
groups each consisting of 8 mice. Ethanol solutions separately
containing the amine derivatives (Ia-1) to (Ia-18) in a
concentration of 0.025% were applied 5 times a week to their
corresponding groups of mice for 6 weeks in a dose of 80 .mu.l. As
a control, ethanol alone was applied in a dose of 80 .mu.l like the
samples.
After completion of the application, the degree of wrinkles was
visually observed to rank the samples in accordance with the
following standard (wrinkle index). The results are shown in Table
3.
(Wrinkle index)
1: Wrinkles were completely removed;
2: Wrinkles were scarcely observed;
3: Wrinkles were somewhat observed;
4: Wrinkles were observed to a great extent.
(2) In order to further analyze the particulars of wrinkles, skin
replicas of the size of 1 cm.sup.2 in diameter were gathered from 3
portions of the back in each of the mice using a Hydrophilic
Exaflex hydrophilic vinylsilicone impression material. Each of
these replicas was held horizontally and illuminated at an angle of
30 degrees from the horizontal direction, thereby finding the
proportion of shadows of the wrinkles as an area percent by means
of an image analyzer. The results are shown collectively in Table
3.
TABLE 3 ______________________________________ Area percent by
Amine derivative Wrinkle index image analysis (%)
______________________________________ Control 3.75 .+-. 0.09 6.42
.+-. 0.63 (Ia-1) 3.00 .+-. 0.15 4.08 .+-. 0.43 (Ia-3) 2.80 .+-.
0.30 2.88 .+-. 0.21 (Ia-4) 3.20 .+-. 0.12 3.88 .+-. 0.38 (Ia-5)
3.00 .+-. 0.15 3.26 .+-. 0.31 (Ia-8) 3.10 .+-. 0.10 3.57 .+-. 0.34
(Ia-9) 2.50 .+-. 0.22 1.69 .+-. 0.16 (Ia-10) 3.30 .+-. 0.20 4.20
.+-. 0.37 (Ia-11) 3.80 .+-. 0.12 5.77 .+-. 0.56 (Ia-12) 3.10 .+-.
0.29 3.57 .+-. 0.33 (Ia-13) 3.30 .+-. 0.30 4.20 .+-. 0.40 (Ia-14)
2.58 .+-. 0.37 1.94 .+-. 0.15 (Ia-15) 2.77 .+-. 0.30 2.53 .+-. 0.22
(Ia-16) 2.90 .+-. 0.18 2.94 .+-. 0.21 (Ia-17) 3.60 .+-. 0.18 5.11
.+-. 0.56 (Ia-18) 3.33 .+-. 0.28 4.29 .+-. 0.41
______________________________________
As apparent from the result shown in Table 3, the wrinkles formed
on the backs of the hairless mice can be removed by applying the
amine derivatives (Ia) thereto.
Example 24
A W/O type cream having the following composition was obtained in
accordance with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Amine derivative (Ia-1)
0.1 (2) Cholesterol 0.5 (3) Cholesteryl isostearate 1.0 (4)
Polyether-modified silicone 1.5 (5) Cyclic silicone 20.0 (6)
Methylphenylpolysiloxane 2.0 (7) Methylpolysiloxane 2.0 (8)
Magnesium sulfate 0.5 (9) 55% Ethanol 5.0 (10) Carboxymethylchithin
(Chithin Liquid 0.5 HV, product of Ichimaru Pharcos Co., Ltd.) (11)
Purified water Balance ______________________________________
(Preparation process)
Components (1)-(7) were heated to 80.degree. C. to melt them, and
the components (8)-(11) were added to the melt. The resultant
mixture was intimately mixed to prepare a W/O type cream.
Example 25
An O/W type cream having the following composition was obtained in
accordance with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Polyoxyethylene (10)
hardened castor oil 1.0 (2) Sorbitan monostearate 0.5 (3) Sodium
stearoylmethyltaurine 0.5 (4) Cetostearyl alcohol 2.0 (5) Stearic
acid 1.8 (6) Amine derivative (Ia-3) 0.001 (7) Cholesterol 1.5 (8)
Cholesteryl isostearate 1.0 (9) Neopentyl glycol dicaprate 8.0 (10)
Methylpolysiloxane 5.0 (11) Glycerol 5.0 (12) Purified water
Balance ______________________________________
(Preparation process)
Components (1)-(10) were heated to 80.degree. C. to melt them, and
the components (11)-(12) were added to the melt. The resultant
mixture was intimately mixed to prepare an O/W type cream.
Example 26
A moisturizing sunscreen cream having the following composition was
obtained in accordance with the below-described preparation
process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Amine derivative (Ia-9)
0.0005 (2) Silicon-coated zinc oxide 7.0 (3) 2-Ethylhexyl
p-methoxycinnamate 3.0 (4) Cholesteryl isostearate 1.0 (5)
Polyether-modified silicone 2.0 (6) Methylpolysiloxane 5.0 (7)
Cyclic silicone 15.0 (8) Magnesium sulfate 1.0 (9) Glycerol 5.0
(10) Purified water Balance
______________________________________
(Preparation process)
Components (1)-(7) were heated to 80.degree. C. to melt them, and
the components (8)-(10) were added to the melt. The resultant
mixture was intimately mixed to prepare a moisturizing sunscreen
cream.
Example 27
A pack having the following composition was obtained in accordance
with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Amine derivative (Ia-16)
hydrochloride 0.05 (2) Polyvinyl alcohol 15.0 (3) Sodium
carboxymethylcellulose 5.0 (4) Propylene glycol 3.0 (5) Ethanol 8.0
(6) Purified water Balance (7) Perfume base 0.5 (8) Antiseptic,
oxidizing agent q.s. ______________________________________
(Preparation process)
Components (1)-(8) were heated to 70.degree. C. to melt them, and
then cooled, thereby preparing a pack.
Example 28
An ointment having the following composition was obtained in
accordance with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Amine derivative (Ia-14)
0.075 (2) White petrolatum Balance (3) Cholesteryl isostearate 3.0
(4) Liquid paraffin 10.0 (5) Glyceryl ether 1.0 (6) Glycerol 10.0
______________________________________
(Preparation process)
Components (1)-(6) were heated to 80.degree. C. to melt them, and
then cooled, thereby preparing an ointment.
The dermatologic preparations according to the present invention,
which were prepared in Examples 24-28, had excellent effects of
preventing the occurrence of wrinkles and smoothing or removing
wrinkles and moreover inhibited parakeratosis of the skin,
epidermic hypertrophy and metabolic aberration of lipid and were
excellent in recovery of normal functions and maintenance of
homeostasis.
Preparation Example 1:
Preparation of 1-(2-hydroxyethylamino)-3-tocopheryloxy-2-propanol
(Ib-1):
[In the general formula (Ib), R.sup.27 : ##STR80##
A 500-ml flask equipped with a reflux condenser, dropping funnel
and stirrer was charged with 61.1 g (1 mol) of ethanolamine and 100
g of ethanol. While heating and stirring the mixture at 80.degree.
C. in a nitrogen atmosphere, a solution of 24.3 g (0.05 mol) of
tocopheryl glycidyl ether in 25 ml of ethanol was added dropwise
over 2 hours. After the contents were heated and stirred further
for 18 hours, excess ethanol was distilled off under reduced
pressure, and the resultant residue was purified by column
chromatography on silica gel, thereby obtaining 23.8 g (yield:
86.9%) of the title compound (Ib-1).
Pale yellow oil.
IR (NaCl, cm.sup.-1): 3312, 2936, 1456, 1414, 1378, 1252, 1088,
1062, 916, 746.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.79-0.90(m,12H) ,
0.94-1.62(m,24H), 1.68-1.87(m,2H), 2.07(s,3H), 2.13(s,3H),
2.17(s,3H), 2.56(br,5H), 2.80-2.89(m,4H), 3.63-3.75(m,4H),
4.07-4.21(m,1H).
Preparation Example 2:
Preparation of
1-(2-hydroxyethylamino)-3-[9,10-(isopropylidenedioxy)octadecyloxy]-2-Propa
nol (Ib-2):
[In the general formula (Ib), R.sup.27 : ##STR81## R.sup.28,
R.sup.29, R.sup.30, R.sup.31, R.sup.32 : H]
A 200-ml flask equipped with a stirrer was charged with 33.05 g
(100 mmol) of methyl 9,10-dihydroxyoctadecanate, 52 g (500 mmol) of
2,2-dimethoxypropane and 0.86 g (5 mmol) of p-toluenesulfonic acid.
The contents were stirred at room temperature for 18 hours and
neutralized with NaHCO.sub.3. Thereafter, the solvent was distilled
off under reduced pressure.
A 500-ml flask equipped with a stirrer and a dropping funnel was
then charged with 3.8 g (100 mmol) of LiAlH.sub.4 and 200 ml of
tetrahydrofuran. While stirring the mixture at room temperature, an
intermediate obtained in the above reaction was added to the
mixture over 20 minutes. The resultant mixture was stirred further
for 1 hour at room temperature. After 12 g of 5% aqueous KOH were
added dropwise to decompose excess LiAlH.sub.4, a salt deposited
was separated by filtration, and the solvent was distilled off
under reduced pressure.
The resultant residue was then transferred to a 300-ml flask
equipped with a stirrer and reflux condenser, which was charged
with 27.8 g (300 mmol) of epichlorohydrin and 1.61 g (5 mmol) of
tetrabutylammonium chloride. While stirring the mixture at
40.degree. C., 33.3 g (400 mmol) of 48% aqueous NaOH were added
dropwise over 3 hours. After the resultant mixture was stirred
further for 2 hours at 40.degree. C., it was washed with water and
concentrated under reduced pressure, and the resultant residue was
purified by column chromatography on silica gel, thereby obtaining
23.9 g (yield: 60.0%) of 9,10-(isopropylideneoxy)octadecyl glycidyl
ether as an intermediate.
A 200-ml flask equipped with a stirrer, reflux condenser and a
dropping funnel was then charged with 30.9 g (506 mmol) of
ethanolamine and 6.5 g of ethanol. While stirring the mixture at
80.degree. C., 13.1 g (32.9 mmol) of
9,10-(isopropylideneoxy)octadecyl glycidyl were added dropwise over
2 hours. After the contents were stirred further for 1 hour, the
reaction mixture was concentrated under reduced pressure, and the
resultant residue was purified by column chromatography on silica
gel, thereby obtaining 12.9 g (yield: 85%) of the title compound
(Ib-2).
Pale yellow oil.
IR (NaCl, cm.sup.-1): 3316, 2924, 2856, 1464, 1370, 1240, 1216
1118, 864, 748.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.88(t,J=6.25 Hz,3H),
1.10-1.70(m,34H), 2.50-2.88(m,4H), 3.00-3.52(m,7H),
3.58-3.78(m,2H), 3.82-4.10(m,3H).
Example 29
Effect of the amine derivatives on wrinkles formed on hairless mice
by exposure to UVB:
Hairless mice (HR/ICR, aged 9 weeks at the beginning of the
experiment) were each exposed to UVB 3 times a week by using 6
Toshiba healthy lamps, 20SE. The amount of energy was measured by
means of a UV-Radiometer UVR-305/365D manufactured by TOKYO OPTICAL
K.K. The dose upon one exposure was determined to be 1 MED or less,
i.e., 65 mj in an amount of energy of 0.28 mM/cm.sup.2. The
exposure was effected for 20 weeks. After confirming the fact that
the mice had got wrinkles at their backs, they were divided into
groups each consisting of 8 mice. Ethanol solutions separately
containing the amine derivatives (Ib-1) and (Ib-2) in a
concentration of 0.025% were applied 5 times a week to their
corresponding groups of mice for 6 weeks in a dose of 80 .mu.l. As
a control, ethanol alone was applied in a dose of 80 .mu.l like the
samples.
After completion of the application, the degree of wrinkles was
visually observed to rank the samples in accordance with the
following standard (wrinkle index). The results are shown in Table
4.
(Wrinkle index; evaluation standard)
1: Wrinkles were completely removed;
2: Wrinkles were scarcely observed;
3: Wrinkles were somewhat observed;
4: Wrinkles were observed to a great extent.
TABLE 4 ______________________________________ Group Wrinkle index
______________________________________ Control 3.75 .+-. 0.09 Amine
derivative (Ib-1) 3.00 .+-. 0.15 Amine derivative (Ib-2) 3.60 .+-.
0.18 ______________________________________
As apparent from the result shown in Table 4, the wrinkles formed
on the backs of the hairless mice can be removed by applying the
amine derivatives (Ib-1), (Ib-2) thereto.
In order to further analyze the particulars of wrinkles, skin
replicas of the size of 1 cm.sup.2 in diameter were gathered from 3
portions of the back in each of the mice using a Hydrophilic
Exaflex hydrophilic vinylsilicone impression material. Each of
these replicas was held horizontally and illuminated at an angle of
30 degrees from the horizontal direction, thereby finding the
proportion of shadows of the wrinkles as an area percent by means
of an image analyzer. The results are shown collectively in Table
5.
TABLE 5 ______________________________________ Area percent by
Group image analysis (%) ______________________________________
Control 6.42 .+-. 0.63 Amine derivative (Ib-1) 3.26 .+-. 0.30 Amine
derivative (Ib-2) 5.14 .+-. 0.49
______________________________________
As apparent from the result shown in Table 5, the wrinkles formed
on the backs of the hairless mice can be removed by applying the
amine derivatives (Ib-1), (Ib-2) thereto.
Example 30
Inhibitory effect of the amine derivatives on DNA synthesis of
epidermic keratinocyte:
(1) Method:
a) Culture of human epidermic keratinocyte:
Human normal keratinocytes (trade name: Epipack) commercially
available from Kurabo Industries Ltd. were purchased and used as
keratinocytes. Incidentally, a medium for human normal
keratinocytes (trade name: K-GM) commercially available from the
said firm was used in the maintenance and subculture of the
cells.
b) Determination of DNA synthesis (thymidine incorporation):
Keratinocytes cultured in a vegetative state in a 24-well plate
were used. A medium in each well was first removed by suction to
add 450 .mu.l of K-GM, to which no pituitary gland extract was
added, to the well, thereby making a medium exchange. Thereafter,
each of the amine derivatives (Ib-1), (Ib-2) obtained in the above
synthesis examples was added thereto. Further, 0.2 .mu.Ci/ml of
[.sup.3 H] thymidine was subsequently added to incubate the culture
for 4 hours. After the supernatant was then removed by suction, and
the well was washed 3 times with PBS(-), 500 .mu.l of 2N NaOH were
added. After the culture was incubated at 37.degree. C. for 10
minutes, an equiamount of 2N HCl was added to neutralize the
culture, and 4 ml of 10% trichloroacetic acid chilled with ice
water were added, followed by leaving at rest for 30 minutes.
Precipitate was collected on a glass filter and then washed 3 times
with 3 ml of 10% trichloroacetic acid chilled with ice water. The
glass filter was washed further once with 3 ml of ethanol chilled
with ice water and then air-dried to measure its radioactivity by a
liquid scintillation counter, thereby calculating the thymidine
incorporation into the cells.
TABLE 6 ______________________________________ Relative amount of
[.sup.3 H] thyimidine incorporated (%)* Amine derivative 10 .mu.M
100 .mu.M ______________________________________ (Ib-1) 21.8 8.2
(Ib-2) 17.3 4.4 ______________________________________ *:
Indicating the relative value where a control is assumed to be
100%.
It was apparent from Table 6 that the thymidine incorporation is
markedly reduced by the addition of the amine derivatives, namely,
that the DNA synthesis of the human epidermic keratinocytes is
inhibited. Besides, the human epidermic keratinocytes treated under
the same conditions as described above were observed on the fourth
day. As a result, it was found that most of the cells turn
insoluble membrane (cornified envelope), i.e., become keratinized.
It is understood from this fact that the amine derivatives
according to the present invention are active in facilitating the
keratinization of epidermis.
Example 31
A W/O type cream having the following composition was obtained in
accordance with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Amine derivative (Ib-1)
0.1 (2) Cholesterol 0.5 (3) Cholesteryl isostearate 1.0 (4)
Polyether-modified silicone 1.5 (5) Cyclic silicone 20.0 (6)
Methylphenylpolysiloxane 2.0 (7) Methylpolysiloxane 2.0 (8)
Magnesium sulfate 0.5 (9) 55% Ethanol 5.0 (10) Carboxymethylchithin
(Chithin Liquid 0.5 HV, product of Ichimaru Pharcos Co., Ltd.) (11)
Purified water Balance ______________________________________
(Preparation process)
Components (1)-(7) were heated to 80.degree. C. to melt them, and
the components (8)-(11) were added to the melt. The resultant
mixture was intimately mixed to prepare a W/O type cream.
Example 32
An O/W type cream having the following composition was obtained in
accordance with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Polyoxyethylene (10)
hardened castor oil 1.0 (2) Sorbitan monostearate 0.5 (3) Sodium
stearoylmethyltaurine 0.5 (4) Cetostearyl alcohol 2.0 (5) Stearic
acid 1.8 (6) Amine derivative (Ib-1) 0.001 (7) Cholesterol 1.5 (8)
Cholesteryl isostearate 1.0 (9) Neopentyl glycol dicaprate 8.0 (10)
Methylpolysiloxane 5.0 (11) Glycerol 5.0 (12) Purified water
Balance ______________________________________
(Preparation process)
Components (1)-(10) were heated to 80.degree. C. to melt them, and
the components (11)-(12) were added to the melt. The resultant
mixture was intimately mixed to prepare an O/W type cream.
Example 33
A sunscreen cream having the following composition was obtained in
accordance with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Amine derivative (Ib-2)
0.05 (2) Silicon-coated zinc oxide 7.0 (3) 2-Ethylhexyl
p-methoxycinnamate 3.0 (4) Cholesteryl isostearate 1.0 (5)
Polyether-modified silicone 2.0 (6) Methylpolysiloxane 5.0 (7)
Cyclic silicone 15.0 (8) Magnesium sulfate 1.0 (9) Glycerol 5.0
(10) Purified water Balance
______________________________________
(Preparation process)
Components (1)-(7) were heated to 80.degree. C. to melt them, and
the components (8)-(10) were added to the melt. The resultant
mixture was intimately mixed to prepare a moisturizing sunscreen
cream.
Example 34
A pack having the following composition was obtained in accordance
with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Amine derivative (Ib-1)
hydrochloride 0.05 (2) Polyvinyl alcohol 15.0 (3) Sodium
carboxymethylcellulose 5.0 (4) Propylene glycol 3.0 (5) Ethanol 8.0
(6) Purified water Balance (7) Perfume base 0.5 (8) Antiseptic,
oxidizing agent q.s. ______________________________________
(Preparation process)
Components (1)-(8) were heated to 70.degree. C. to melt them, and
then cooled, thereby preparing a pack.
Example 35
An ointment having the following composition was obtained in
accordance with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Amine derivative (Ib-2)
0.2 (2) White petrolatum Balance (3) Cholesteryl isostearate 3.0
(4) Liquid paraffin 10.0 (5) Glyceryl ether 1.0 (6) Glycerol 10.0
______________________________________
(Preparation process)
Components (1)-(6) were heated to 80.degree. C. to melt them, and
then cooled, thereby preparing an ointment.
The dermatologic preparations, which were prepared in Examples
31-35 and comprised the amine derivative (Ib-1) or (Ib-2) according
to the present invention as an effective ingredient, had excellent
effects of preventing the occurrence of wrinkles and smoothing or
removing wrinkles and moreover inhibited parakeratosis of the skin,
epidermic hypertrophy and metabolic aberration of lipid and were
excellent in recovery of normal functions and maintenance of
homeostasis.
Preparation Example 3:
Preparation of 1-(2-hydroxyethylamino)-3-methoxy-2-propanol (Ic-1)
[In the general formula (Ic), R.sup.33 =CH.sub.3 ; R.sup.34
.dbd.R.sup.35 .dbd.R.sup.36 .dbd.R.sup.37 .dbd.R.sup.38 =H]:
##STR82##
A 1000-ml two-necked flask equipped with a reflux condenser and
100-ml dropping funnel was charged with 517 g (8.46 mol) of
ethanolamine and 103 g of ethanol. While heating and stirring the
mixture at 80.degree. C. in a nitrogen atmosphere, 50.0 g (0.57
mol) of methyl glycidyl ether were added dropwise over 2 hours.
After the contents were heated and stirred further for 2 hours, the
reaction mixture was subjected to distillation, thereby obtaining
73.0 g (yield: 80%) of the title compound (Ic-1).
Colorless solid.
Melting point: 41.5.degree.-42.5.degree. C.
IR (NaCl, cm.sup.-1): 3400, 2932, 2850, 1452, 1414, 1102, 1106,
958.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.52-2.82(m,4H),
3.25-3.42(m,5H) , 3.50-4.15(m,6H).
Preparation Example 4:
The amine derivative (Ic-1) was reacted with hydrochloric acid,
glycolic acid or lactic acid in ethanol, and the solvent was
distilled off under reduced pressure, thereby preparing the
hydrochloride, glycolate or lactate of the amine derivative (Ic-1).
Hydrochloride of (Ic-1):
Pale yellow oil.
IR (NaCl, cm.sup.-1): 3344, 2928, 1664, 1584, 1446, 1190, 1078.
.sup.1 H-NMR (D.sub.2 O, .delta.): 3.07-3.31(m,4H), 3.41(s,3H),
3.55(d,2H,J=4.3 Hz), 3.85-3.90(m,2H), 4.10-4.21(m,1H).
Lactate of (Ic-1):
Colorless oil.
IR (NaCl, cm.sup.-1): 3340, 2944, 1588, 1456, 1418, 1198, 1124,
1038, 966, 852, 772.
.sup.1 H-NMR (CDCl, .sub.3 .delta.): 1.29-1.39(m,3H),
2.80-4.35(m,18H).
Glycolate of (Ic-1):
Colorless oil.
IR (NaCl, cm.sup.-1): 3320, 2904, 1600, 1446, 1322, 1198, 1076,
968, 918, 748, 690.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.92-3.09(m,4H), 3.38(s,3H),
3.43-3.49(m,2H), 3.82-4.18(m,10H).
Preparation Example 5:
A reaction was conducted in the same manner as in Preparation
Example 3 except that allyl glycidyl ether was used in place of
methyl glycidyl ether in Preparation Example 3, thereby
synthesizing the following amine derivative (Ic-2). ##STR83##
Colorless oil.
IR (NaCl cm.sup.-1): 3320, 2920, 2860, 1648, 1460, 1428, 1356,
1106, 1056, 1000, 932, 868.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.57-2.77(m,4H),
3.40-4.02(m,2H), 5.16-5.31(m,2H), 5.80-6.00(m,1H).
Preparation Example 6:
Preparation of
1-((1,1-bis(hydroxymethyl)ethyl)amino)-3-methoxy-2-propanol (Ic-3)
[In the general formula (Ic), R.sup.33 .dbd.R.sup.35 =CH.sub.3 ;
R.sup.36 =CH.sub.2 OH; R.sup.34 .dbd.R.sup.37 .dbd.R.sup.38 =H]:
##STR84##
A 300-ml two-necked flask equipped with a reflux condenser and
10-ml dropping funnel was charged with 78.9 g (0.75 mol) of
2-amino-2-methyl-1,3-propanediol and 15.8 g of ethanol. While
heating and stirring the mixture at 80.degree. C. in a nitrogen
atmosphere, 4.4 g (0.05 mol) of methyl glycidyl ether were added
dropwise over 3 hours. After completion of the reaction, ethanol
was distilled off under reduced pressure, and excess
2-amino-2-methyl-1,3-propanediol was removed by crystallization.
The resultant residue was then purified by flash column
chromatography on silica gel, thereby obtaining 9.1 g (yield: 94%)
of the title compound (Ic-3).
Pale yellow oil.
IR (NaCl, cm.sup.-1): 3380, 2936, 2888, 1456, 1384, 1326, 1196,
1128, 1044, 962, 864, 750.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.94(s,3H), 2.55(dd,
1H,J=8.3,11.7 Hz), 2.66(dd, 1H,J=3.5,11.7 Hz),
3.28-3.94(m,14H).
Preparation Example 7:
A reaction was conducted in the same manner as in Preparation
Example 6 except that tris(hydroxymethyl)aminomethane and water
were used in place of 2-amino-2-methyl-1,3-propanediol and ethanol,
respectively, in Preparation Example 6, thereby synthesizing the
following amine derivative (Ic-4). ##STR85##
Pale yellow oil.
IR (NaCl, cm.sup.-1): 3368, 2892, 1462, 1196, 1032, 964, 870,
751.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.63(dd,1H,J=7.7,12.1 Hz),
2.75(dd,1H,J=3.6,12.1 Hz), 3.21-3.94(m,17H).
Preparation Example 8:
Preparation of
1-(N-(2-hydroxyethyl)-N-methylamino)-3-methoxy-2-propanol (Ic-5)
[In the general formula (Ic), R.sup.33 .dbd.R.sup.34 =CH.sub.3 ;
R.sup.35 .dbd.R.sup.36 .dbd.R.sup.37 .dbd.R.sup.38 =H]:
##STR86##
A 100-ml two-necked flask equipped with a reflux condenser was
charged with 8.8 g (0.1 tool) of methyl glycidyl ether, 9.0 g (0.12
mol) of 2-(methylamino)ethanol and 1.8 g of ethanol. The contents
were heated and stirred at 80.degree. C. for 3 hours in a nitrogen
atmosphere. After completion of the reaction, the reaction mixture
was subjected to distillation, thereby obtaining 14.5 g (yield:
89%) of the title compound (Ic-5).
Colorless oil.
IR (NaCl, cm.sup.-1): 3396, 2892, 1448, 1324, 1192, 1030, 874.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.33(s,3H) , 2.37-2.72(m,4H),
3.32-3.96(m,10H) .
Preparation Example 9:
Reactions were conducted in the same manner as in Preparation
Example 8 except that diethanolamine and allyl glycidyl ether were
used respectively in place of 2-(methylamino)ethanol in Preparation
Example 8, thereby synthesizing the following amine derivatives
(Ic-6) and (1c-7).
Further, the amine derivative (Ic-7) was hydrogenated by means of a
Pd/C catalyst, thereby synthesizing the following amine derivative
(Ic-8). ##STR87## (Ic-6):
Colorless oil.
IR (NaCl, cm.sup.-1): 3340, 2884, 1442, 1362, 1248, 1030.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.37-2.83(m,6H),
3.37-3.96(m,10H), 4.74(bs,3H).
(Ic-7):
Colorless oil.
IR (NaCl, cm.sup.-1): 3420, 3088, 2948, 2856, 1650, 1462, 1424,
1328, 1264, 1198, 1082, 1034, 926, 874, 800.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.32(s,3H), 2.38-2.71(m,4H),
3.37-3.66(m,6H), 3.86-4.05(m,3H), 5.16-5.33(m,2H).
(Ic-8):
Colorless oil.
IR (NaCl, cm.sup.-1): 3432, 2948, 2872, 1466, 1118, 1084, 1036,
956, 872.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.92(t,3H,J=7.4 Hz),
1.60(tq,2H,J=7.4,7.4 Hz), 2.33(s,3H), 2.39-2.72(m,4H),
3.35-3.49(m,6H), 3.64(t,2H,J=5.3 Hz), 3.86-3.97(m,1H).
Preparation Example 10:
Preparation of
1-(N-benzyl-N-(2-hydroxyethyl)amino)-3-(2,3-dihydroxypropyloxy)-2-propanol
(Ic-9)[In the general formula (Ic), R.sup.33 =HOCH.sub.2
CH(OH)CH.sub.2 ; R.sup.34 =C.sub.6 H.sub.5 CH.sub.2 ; R.sup.35
.dbd.R.sup.36 .dbd.R.sup.37 .dbd.R.sup.38 =H]: ##STR88##
A 100-ml two-necked flask equipped with a reflux condenser was
charged with 3.7 g (0.025 mol) of 2,3-dihydroxypropyl glycidyl
ether, 3.8 g (0.025 mol) of 2-benzylaminoethanol and 0.8 g of
ethanol. The contents were heated and stirred at 80.degree. C. for
3 hours in a nitrogen atmosphere. After completion of the reaction,
ethanol was distilled off under reduced pressure, and the resultant
residue was purified by flash column chromatography on silica gel,
thereby obtaining 5.3 g (yield: 71%) of the title compound
(Ic-9).
Yellow oil.
IR (NaCl, cm.sup.-1): 3400, 3032, 2880, 1652, 1604, 1498, 1456,
1372, 1330, 1258, 1126, 1048, 870, 794, 740, 698.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.48-2.80(m,4H),
3.33-4.03(m,16H), 7.21-7.36(m,5H)
Preparation Example 11:
A reaction was conducted in the same manner as in Preparation
Example 10 except that methyl glycidyl ether and N-methylglucamine
were used in place of 3,3-dihydroxypropyl glycidyl ether and
2-benzylaminoethanol, respectively, in Preparation Example 10,
thereby synthesizing the following amine derivative (Ic-10).
##STR89##
Pale yellow oil.
IR (NaCl, cm.sup.-1): 3344, 2920, 1630, 1434, 1078, 870.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.33, 2.34(s, total 3H),
2.49-2.64(m,4H), 3.30-4.07(m,12H).
Example 36
Effect of the amine derivatives on wrinkles formed on hairless mice
by exposure to UVB:
Hairless mice (HR/ICR, aged 9 weeks at the beginning of the
experiment) were each exposed to UVB 3 times a week by using 6
Toshiba healthy lamps, 20SE. The amount of energy was measured by
means of a UV-Radiometer UVR-305/365D manufactured by TOKYO OPTICAL
K.K. The dose upon one exposure was determined to be 1 MED or less,
i.e., 65 mj in an amount of energy of 0.28 mM/cm.sup.2. The
exposure was effected for 20 weeks. After confirming the fact that
the mice had got wrinkles at their backs, they were divided into
groups each consisting of 8 mice. Ethanol solutions separately
containing the amine derivatives (Ic-1) to (Ic-10) in a
concentration of 0.025% were applied 5 times a week to their
corresponding groups of mice for 6 weeks in a dose of 80 .mu.l. As
a control, ethanol alone was applied in a dose of 80 .mu.l like the
samples.
After completion of the application, the degree of wrinkles was
visually observed to rank the samples in accordance with the
following standard (wrinkle index). The results are shown in Table
7.
(Wrinkle index; evaluation standard)
1: Wrinkles were completely removed;
2: Wrinkles were scarcely observed;
3: Wrinkles were somewhat observed;
4: Wrinkles were observed to a great extent.
TABLE 7 ______________________________________ Group Wrinkle index
______________________________________ Control 3.75 .+-. 0.09 Amine
derivative (Ic-1) 2.00 .+-. 0.42 Amine derivative (Ic-2) 2.25 .+-.
0.35 Amine derivative (Ic-3) 2.50 .+-. 0.25 Amine derivative (Ic-4)
2.63 .+-. 0.25 Amine derivative (Ic-5) 2.58 .+-. 0.42 Amine
derivative (Ic-6) 3.12 .+-. 0.25 Amine derivative (Ic-7) 2.50 .+-.
0.25 Amine derivative (Ic-8) 2.25 .+-. 0.25 Amine derivative (Ic-9)
2.25 .+-. 0.18 Amine derivative (Ic-10) 3.00 .+-. 0.35
______________________________________
As apparent from the result shown in Table 7, the wrinkles formed
on the backs of the hairless mice were able to be removed by
applying the amine derivatives
(Ic-1) to (IC-10) thereto.
In order to further analyze the particulars of wrinkles, skin
replicas of the size of 1 cm.sup.2 in diameter were gathered from 3
portions of the back in each of the mice using a Hydrophilic
Exaflex hydrophilic vinylsilicone impression material. Each of
these replicas was held horizontally and illuminated at an angle of
30 degrees from the horizontal direction, thereby finding the
proportion of shadows of the wrinkles as an area percent by means
of an image analyzer. The results are shown in Table 8.
TABLE 8 ______________________________________ Area percent by
Group image analysis (%) ______________________________________
Control 6.42 .+-. 0.63 Amine derivative (Ic-1) 1.91 .+-. 0.50 Amine
derivative (Ic-2) 3.25 .+-. 0.74 Amine derivative (Ic-3) 2.84 .+-.
0.64 Amine derivative (Ic-4) 3.76 .+-. 0.75 Amine derivative (Ic-5)
2.52 .+-. 0.54 Amine derivative (Ic-6) 4.03 .+-. 0.58 Amine
derivative (Ic-7) 3.16 .+-. 0.72 Amine derivative (Ic-8) 3.33 .+-.
0.56 Amine derivative (Ic-9) 3.25 .+-. 0.47 Amine derivative
(Ic-10) 3.93 .+-. 0.56 ______________________________________
As apparent from the result shown in Table 8, the wrinkles formed
on the backs of the hairless mice can be removed by applying the
amine derivatives
(Ic-1) to (Ic-10) thereto.
Example 37
Inhibitory effect of the amine derivatives on DNA synthesis of
epidermic keratinocyte:
(1) Method:
a) Culture of human epidermic keratinocyte:
Human normal keratinocytes (trade name: Epipack) commercially
available from Kurabo Industries Ltd. were purchased and used as
keratinocytes. Incidentally, a medium for human normal
keratinocytes (trade name: K-GM) commercially available from the
said firm was used in the maintenance and subculture of the
cells.
b) Determination of DNA synthesis (thymidine incorporation):
Keratinocytes cultured in a vegetative state in a 24-well plate
were used. A medium in each well was first removed by suction to
add 450 .mu.l of K-GM, to which no pituitary gland extract was
added, to the well, thereby making a medium exchange. Thereafter,
each of the amine derivatives
(Ic-1) to (Ic-10) obtained in the above synthesis examples was
added thereto. Further, 0.2 .mu.Ci/ml of [.sup.3 H] thymidine was
subsequently added to incubate the culture for 4 hours. After the
supernatant was then removed by suction, and the well was washed 3
times with PBS(-), 500 .mu.l of 2N NaOH were added. After the
culture was incubated at 37.degree. C. for 10 minutes, an
equiamount of 2N HCl was added to neutralize the culture, and 4 ml
of 10% trichloroacetic acid chilled with ice water were added,
followed by leaving at rest for 30 minutes.
Precipitate was collected on a glass filter and then washed 3 times
with 3 ml of 10% trichloroacetic acid chilled with ice water. The
glass filter was washed further once with 3 ml of ethanol chilled
with ice water and then air-dried to measure its radioactivity by a
liquid scintillation counter, thereby calculating the thymidine
incorporation into the cells.
TABLE 9 ______________________________________ Relative amount of
[.sup.1 H] thyimidine incorporated (%)* Amine derivative 10 .mu.M
100 .mu.M ______________________________________ Amine derivative
(Ic-1) 76.2 .+-. 5.5 42.0 .+-. 1.5 Amine derivative (Ic-2) 67.6
.+-. 5.5 33.1 .+-. 1.2 Amine derivative (Ic-3) 81.7 .+-. 4.9 38.9
.+-. 2.7 Amine derivative (Ic-4) 87.3 .+-. 5.2 46.7 .+-. 2.8 Amine
derivative (Ic-5) 65.7 .+-. 4.3 39.1 .+-. 1.5 Amine derivative
(Ic-6) 78.3 .+-. 4.8 42.7 .+-. 1.5 Amine derivative (Ic-7) 63.9
.+-. 4.2 31.2 .+-. 1.2 Amine derivative (Ic-8) 75.0 .+-. 4.6 40.7
.+-. 1.3 Amine derivative (Ic-9) 57.5 .+-. 4.1 35.9 .+-. 1.2 Amine
derivative (Ic-10) 81.9 .+-. 5.1 45.9 .+-. 1.7
______________________________________ *: Indicating the relative
value where a control is assumed to be 100%.
It was apparent from Table 9 that the thymidine incorporation is
markedly reduced by the addition of the amine derivatives, namely,
that the DNA synthesis of the human epidermic keratinocytes is
inhibited. Besides, the human epidermic keratinocytes treated under
the same conditions as described above were observed on the fourth
day. As a result, it was found that most of the cells turn
insoluble membrane (cornified envelope), i.e., become keratinized.
It is understood from this fact that the amine derivatives
according to the present invention are active in facilitating the
keratinization of epidermis.
Example 38
A W/O type cream having the following composition was obtained in
accordance with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) One of amine derivatives
(Ic-1)-(Ic-10) 0.08 (2) Cholesterol 0.5 (3) Cholesteryl isostearate
1.0 (4) Polyether-modified silicone 1.5 (5) Cyclic silicone 20.0
(6) Methylphenylpolysiloxane 2.0 (7) Methylpolysiloxane 2.0 (8)
Magnesium sulfate 0.5 (9) 55% Ethanol 5.0 (10) Carboxymethylchithin
(Chithin Liquid 0.5 HV, product of Ichimaru Pharcos Co., Ltd.) (11)
Purified water Balance ______________________________________
(Preparation process)
Components (1)-(7) were heated to 80.degree. C. to melt them, and
the components (8)-(11) were added to the melt. The resultant
mixture was intimately mixed to prepare a W/O type cream.
Example 39
An O/W type cream having the following composition was obtained in
accordance with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Polyoxyethylene (10)
hardened castor oil 1.0 (2) Sorbitan monostearate 0.5 (3) Sodium
stearoylmethyltaurine 0.5 (4) Cetostearyl alcohol 2.0 (5) Stearic
acid 1.8 (6) One of amine derivatives (Ic-1)-(Ic-10) 0.001 (7)
Cholesterol 1.5 (8) Cholesteryl isostearate 1.0 (9) Neopentyl
glycol dicaprate 8.0 (10) Methylpolysiloxane 5.0 (11) Glycerol 5.0
(12) Purified water Balance
______________________________________
(Preparation process)
Components (1)-(10) were heated to 80.degree. C. to melt them, and
the components (11)-(12) were added to the melt. The resultant
mixture was intimately mixed to prepare an O/W type cream.
Example 40
A sunscreen cream having the following composition was obtained in
accordance with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) One of amine derivatives
(Ic-1)-(Ic-10) 0.0005 (2) Silicon-coated zinc oxide 7.0 (3)
2-Ethylhexyl p-methoxycinnamate 3.0 (4) Cholesteryl isostearate 1.0
(5) Polyether-modified silicone 2.0 (6) Methylpolysiloxane 5.0 (7)
Cyclic silicone 15.0 (8) Magnesium sulfate 1.0 (9) Glycerol 5.0
(10) Purified water Balance
______________________________________
(Preparation process)
Components (1)-(7) were heated to 80.degree. C. to melt them, and
the components (8)-(10) were added to the melt. The resultant
mixture was intimately mixed to prepare a moisturizing sunscreen
cream.
Example 41
A pack having the following composition was obtained in accordance
with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Hydrochloride of one of
amine 0.05 derivatives (Ic-1)-(Ic-10) (2) Polyvinyl alcohol 15.0
(3) Sodium carboxymethylcellulose 5.0 (4) Propylene glycol 3.0 (5)
Ethanol 8.0 (6) Purified water Balance (7) Perfume base 0.5 (8)
Antiseptic, oxidizing agent q.s.
______________________________________
(Preparation process)
Components (1)-(8) were heated to 70.degree. C. to melt them, and
then cooled, thereby preparing a pack.
Example 42
An ointment having the following composition was obtained in
accordance with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) One of amine derivatives
(Ic-1)-(Ic-10) 0.075 (2) White petrolatum Balance (3) Cholesteryl
isostearate 3.0 (4) Liquid paraffin 10.0 (5) Glyceryl ether 1.0 (6)
Glycerol 10.0 ______________________________________
(Preparation process)
Components (1)-(6) were heated to 80.degree. C. to melt them, and
then cooled, thereby preparing an ointment.
The dermatologic preparations according to the present invention,
which were prepared in Examples 38-42, had excellent effects of
preventing the occurrence of wrinkles and smoothing or removing
wrinkles and moreover inhibited parakeratosis, epidermic
hypertrophy and metabolic aberration of lipid and were excellent in
recovery of normal functions and maintenance of homeostasis.
Preparation Example 12:
Preparation of
1-(2-hydroxyethylamino)-2-methyl-3-tetradecyloxy-2-propanol
(IIa-1): ##STR90##
A 200-ml flask equipped with a stirrer was charged with 10 g (46.6
mmol) of tetradecanol, 50 ml of dimethylformamide, 2.86 g (71.5
mmol) of 60% NaH and 5.96 g (65.8 mmol) of methallyl chloride. The
contents were stirred at 60.degree. C. for 15 hours. After
completion of the reaction, the reaction mixture was added with
water and subjected to extraction with hexane, and the solvent was
distilled off under reduced pressure. The resultant residue was
charged into a 300-ml flask equipped with a stirrer, and 12.24 g
(70.9 mmol) of m-chloroperbenzoic acid and 200 ml of
dichloromethane were added thereto. The resultant mixture was
stirred at room temperature for 19 hours. Solids formed were
separated by filtration, and the resultant solution was
concentrated under reduced pressure and then purified by column
chromatography on silica gel, thereby obtaining 10.54 g (yield:
79.4%) of 1,2-epoxy-2-methyl-3-tetradecyloxypropane as an
intermediate.
A 100-ml flask equipped with a stirrer and dropping funnel was then
charged with 16.8 g (280 mmol) of ethanolamine and 15 g of ethanol.
While stirring the mixture at 80.degree. C., an ethanol solution of
5.00 g (17.6 mmol) of 1,2-epoxy-2-methyl-3-tetradecyloxypropane was
added dropwise over 3 hours. The contents were stirred further for
2 hours. The resultant reaction mixture was concentrated under
reduced pressure, and the resultant residue was purified by column
chromatography on silica gel, thereby obtaining 4.13 g (yield: 68%)
of the title compound.
Pale yellow solid.
Melting point: 49.1.degree.-50.2.degree. C.
IR (KBr, cm.sup.-1): 3324, 2924, 2856, 1462, 1378, 1110, 1058.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.88(t,J=6.4 Hz,3H),
1.08-1.68(m,27H), 3.34(s,2H), 3.43 (t,J=6.6 Hz,2H), 3.70(td,J=5.1
Hz,1.2 Hz,2H), 3.99(brs,3H).
Preparation Example 13:
Reactions were conducted in the same manner as in Preparation
Example 12 except that crotyl chloride, prenyl chloride and
3-methyl-3-butenyl p-toluenesulfonate were respectively used in
place of methallyl chloride in Preparation Example 12, thereby
preparing the following amine derivatives (IIa-2)-(IIa-4).
##STR91## (IIa-2):
Pale yellow solid.
Melting point: 37.5.degree.-38.8.degree. C.
IR (KBr, cm.sup.-1): 3464, 2920, 2852, 1466, 1376, 1102, 1054.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.88(t,J=6.4 Hz,3H),
1.07(d,J=6.5 Hz,3H), 1.22-1.82(m,24H), 2.60-3.15(m,6H),
3.32-3.39(m,7H).
(IIa-3):
Pale yellow oil.
IR (NaCl, cm.sup.-1): 3320, 2924, 2852, 1462, 1382, 1108.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.88(t,J=6.4 Hz,3H),
1.10(s,3H), 1.16(s,3H), 1.18-1.70(m,24H), 2.72=2.86(m,2H),
2.92-3.35(m,3H), 3.36-3.76(m,7H).
(IIa-4):
Pale yellow oil.
IR (NaCl, cm.sup.-1): 3380, 2928, 2856, 1462, 1372, 1112, 1060.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.82-0.95(m,3H),
1.11-1.42(m,21H), 1.48-1.74(m,3H), 1.87-2.03(m,1H), 2.56(d,J=11.7
Hz,1H), 2.58(br,3H), 2.62(d,J=11.7 Hz,1H), 2.77-2.85(m,2H),
3.41(d,J=6.5 Hz,2H), 3.54-3.75(m,4H).
Preparation Example 14:
Preparation of 1-(3-hydroxypropylamino)-3-tetradecyloxy-2-propanol
(II-5): ##STR92##
A 300-ml two-necked flask equipped with a stirrer and a dropping
funnel was charged with 25.1 g (0.33 mol) of 3-amino-1-propanol and
6.00 g of ethanol, and the contents were heated and stirred at
80.degree. C. in a nitrogen atmosphere. After 9.00 g (33 mmol) of
tetradecyl glycidyl ether were added dropwise over 2 hours, the
resultant mixture was stirred further for 1 hour. The reaction
mixture was poured into 400 ml of ice water and stirred for 1 hour.
Crystals formed were then collected by filtration and
recrystallized from methanol, thereby obtaining 15.4 g (yield: 92%)
of the title compound (IIa-5).
Colorless solid.
Melting point: 63.9.degree.-65.2.degree. C.
IR (KBr, cm.sup.-1): 3320, 2920, 2852, 1462, 1306, 1116, 1052.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.88(t,J=6.29 Hz,3H),
1.16-1.80(m,26H), 2.46-3.50(m,11H), 3.66-3.96(m,3H).
Preparation Example 15:
Reactions were conducted in the same manner as in Preparation
Example 14 except that 5-amino-1-propanol,
2-(2-aminoethoxy)ethanol,
3-(3-amino-2-hydroxypropyl)-1,2-propanediol and
3-amino-1-glucopyranosyloxy-2-propanol were respectively used in
place of 3-amino-1-propanol in Preparation Example 14, thereby
preparing the following amine derivatives (IIa-6)-(IIa-9).
##STR93## (IIa-6):
Colorless solid.
Melting point: 69.4.degree.-70.5.degree. C.
IR (KBr, cm.sup.-1): 3296, 2920, 2852, 1462, 1378, 1116, 1056.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.88(t,J=5.66 Hz,3H),
1.10-1.68(m,30H), 2.50-2.76(m,4H), 3.28-3.50(m,7H),
3.56-3.68(m,2H), 3.77-3.92(m,1H).
(IIa-7):
Colorless solid.
Melting point: 56.5.degree.-57.6.degree. C.
IR (KBr, cm.sup.-1): 3376, 2920, 2852, 1466, 1378, 1126, 1070.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.88(t,J=6.29 Hz,3H),
1.10-1.68(m,24H), 2.50-2.88(m,4H), 2.86-3.76(m,13H),
3.80-3.98(m,1H).
(IIa-8):
Colorless solid.
Melting point: 111.8.degree.-113.0.degree. C.
IR (KBr, cm.sup.-1): 3440, 2924, 2856, 1470, 1124.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.86(t,J=6.40 Hz,3H),
1.20-1.41(m,28H), 2.48-2.57(m,4H), 3.23-3.60(m,15H),
3.67-3.90(m,1H).
(IIa-9):
Colorless solid.
IR (KBr, cm.sup.-1): 3368, 2920, 2852, 1470, 1120, 1070, 1032.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.85-1.70(m,31H),
2.40-5.00(m,26H).
Preparation Example 16:
Preparation of
4-(2-hydroxyethylamino)-1-dodecyloxy-2-methyl-2-butanol (IIa-10):
##STR94##
A 100-ml flask equipped with a stirrer was charged with 11.18 g (60
mmol) of 1-dodecanol, 0.20 g (5 mmol) of 60% NaH and 3.73 g (20
mmol) of 1,2-epoxy-2-methyl-4-(2-tetrahydropyranyloxy)butane. The
contents were stirred at 20.degree. C. for 16 hours, and excess
1-dodecanol was distilled off under reduced pressure. The resultant
reaction mixture was then added with water and subjected to
extraction with isopropyl ether, and the solvent was distilled off
under reduced pressure. The resultant residue was added with 100 ml
of methanol and 1.01 g (4 mmol) of pyridinium p-toluenesulfonate,
and the mixture was stirred at 40.degree. C. for 24 hours and
neutralized with an aqueous solution of NaHCO.sub.3, followed by
extraction with isopropyl ether. The resultant extract was
concentrated under reduced pressure.
A 200-ml flask equipped with a stirrer was then charged with the
resultant residue and 70 ml of pyridine, and 3.82 g (20 mmol) of
p-toluenesulfonyl chloride were added at 5.degree. C. The mixture
was stirred for 6 hours. The reaction mixture was then added with
water and subjected to extraction with isopropyl ether, followed by
concentration under reduced pressure. The resultant residue was
charged into a 200-ml flask equipped with a stirrer, and 24.4 g
(0.4 mol) of ethanolamine and 50 ml of ethanol were added thereto,
followed by stirring at 80.degree. C. for 18 hours. After
completion of the reaction, the reaction mixture was added with
aqueous KOH and subjected to extraction with chloroform, followed
by concentration under reduced pressure. The resultant residue was
purified by column chromatography on silica gel, thereby obtaining
2.00 g (yield: 30.2%) of the title compound (IIa-10).
Pale yellow paste.
IR (NaCl, cm.sup.-1): 3380, 2920, 2852, 1462, 1378, 1110.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.82-0.94(m,3H),
1.14-1.41(m,21H), 1.46-1.97(m,4H), 2.83-2.94(m,2H), 2.99(t,J=6.3
Hz,2H), 3.26(d,J=9.1 Hz,1H), 3.30(d,J=9.1 Hz,1H), 3.43(t,J=6.6
Hz,2H), 3.52-3.81(m,2H), 4.46(br,3H).
Preparation Example 17:
Preparation of (3-tetradecyloxy-2-hydroxypropylamino)acetic acid
hydrochloride [(IIa-11) hydrochloride]: ##STR95##
A 300-ml two-necked flask equipped with a stirrer was charged with
7.51 g (0.1 mol) of glycine, 8.3 g (0.1 mol) of 48% NaOH and 200 ml
of ethanol. While stirring the mixture at 80.degree. C., an ethanol
solution of 2.70 g (10 mmol) of tetradecyl glycidyl ether was
added, and the resultant mixture was stirred for 3 hours. After
ethanol was distilled off under reduced pressure, methanol and
hydrochloric acid was added to the mixture to acidify it. The
mixture was subjected to extraction with chloroform. The resultant
extract was concentrated under reduced pressure, and the residue
was then purified by column chromatography on silica gel, thereby
obtaining 1.17 g (yield: 30.7%) of the title compound [(IIa-10)
hydrochloride].
Colorless solid.
Melting point: 180.degree. C. (decomposed).
(KBr, cm.sup.-1): 3340, 3008, 2916, 2852, 1750, 1594, 1468, 1424,
1364, 1274, 1224, 1130.
.sup.1 H-NMR (CDCl.sub.3 :CD.sub.3 OD=2:1, .delta.):
0.80-0.99(m,3H), 1.09-1.74(m,24H), 3.00-3.33(m,2H),
3.40-3.62(m,4H), 3.71-3.92(m,2H), 3.98-4.20(m,1H).
Preparation Example 18:
A reaction was conducted in the same manner as in Preparation
Example 14 except that dimethyl 2-amino-butanedioate was used in
place of 3-amino-1-propanol in Preparation Example 14, thereby
synthesizing the following amine derivative (IIa-12). This product
was further reacted with hydrochloric acid in ethanol, and the
solvent was distilled off under reduced pressure, thereby preparing
the hydrochloride of the amine derivative (IIa-12). ##STR96##
Colorless solid.
IR (KBr, cm.sup.-1): 3356, 2920, 2852, 1734, 1464, 1254, 1214,
1138, 1116.
.sup.1 H-NMR (CDCl.sub.3 ; CD.sub.3 OD, .delta.): 0.80(t,J=6.6
Hz,3H), 1.08-1.64(m,28H), 2.35-2.75(m,3H), 2.80-3.32(m,2H),
3.34-3.62(m,2H), 3.64-3.90(m,10H), 4.04-4.22(m,1H).
Preparation Example 19:
Preparation of 2-(3-methyl-branched
isostearyloxy-2-methoxypropylamino)-1-ethanol (IIa-13): ##STR97##
(in the formula, .alpha. nd .beta. denote number satisfying the
following relationship: .alpha.+.beta.=11-17, .alpha.=4-10,
.beta.=5-11, and having a distribution that the peaks of .alpha.
and .beta. are 7 and 8, respectively.)
A 100-ml flask equipped with a stirrer was charged with 3.59 g (10
mmol) of 3-methyl-branched isostearyloxy-2-methoxy-1-propanol and
30 ml of pyridine, and 3.82 g (20 mmol) of p-toluenesulfonyl
chloride were added at 5.degree. C., followed by stirring for 6
hours. The reaction mixture was added with water and subjected to
extraction with isopropyl ether, and the solvent was distilled off
under reduced pressure. The resultant residue was charged into a
100-ml flask equipped with a stirrer, to which 12.2 g (0.2 mol) of
ethanolamine and 50 ml of ethanol were added, followed by stirring
at 80.degree. C. for 18 hours. After completion of the reaction,
aqueous KOH was added, extraction with chloroform was conducted,
and the solvent was distilled off under reduced pressure. The
resultant residue was purified by column chromatography on silica
gel, thereby obtaining 2.58 g (yield: 64.2%) of the title compound
(IIa-13).
Pale yellow oil.
IR (NaCl, cm.sup.-1): 3316, 2924, 2856, 1456, 1114.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.75-0.98(m,6H),
1.00-1.76(m,29H), 2.52(brs,2H), 2.62-2.88 (m,4H), 3.30-3.68
(m,10H).
Preparation Example 20:
Preparation of
N-(2-hydroxyethyl)-N,N-dimethyl-N-[3-(methyl-branched
isostearyloxy)-2-hydroxypropyl]ammonium iodide (IIb-1): ##STR98##
(in the formula, .alpha. and .beta. have the same meaning as
defined above.)
A 300-ml flask equipped with a stirrer was charged with 5.05 g
(12.6 mmol) of 3-(methyl-branched
isostearyl-1-[N-methyl-N-2-(hydroxyethyl)amino]-2-propanol prepared
from methyl-branched isostearyl glycidyl ether and
N-methylethanolamine in the same manner as in Preparation Example
14, and 100 ml of diethyl ether. While stirring the contents at
0.degree. C., 9.13 g (64.3 mmol) of iodomethane were added, and the
resultant mixture was stirred further for 14 hours at room
temperature. The resultant reaction mixture was concentrated under
reduced pressure, and the residue was purified by column
chromatography on silica gel, thereby obtaining 3.01 g (yield: 44%)
of the title compound (IIb-1).
Yellow oil.
IR (NaCl, cm.sup.-1): 3360, 2920, 2856, 1464, 1368, 1112, 970.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.72-0.96(m,6H),
0.98-1.80(m,29H), 3.30-3.75(m,12H), 3.80-4.25 (m,6H),
4.42-4.60(m,1H).
Preparation Example 21:
Preparation of
N-(2-hydroxypropyl)-N,N-dimethyl-N-[3-(methyl-branched
isostearyloxy)-2-methoxypropyl]ammonium bromide (IIb-2): ##STR99##
(in the formula, .alpha. and .beta. have the same meaning as
defined above.)
A 100-ml flask equipped with a stirrer was charged with 1.00 g (2.5
mmol) of the amine derivative (IIa-13) obtained in Preparation
Example 19, 2.33 g (25 mmol) of methyl bromide and 300 mol of
ethanol, and the contents were stirred at 50.degree. C. for 72
hours. The resultant reaction mixture was concentrated under
reduced pressure, and the residue was purified by column
chromatography on silica gel, thereby obtaining 0.78 g (yield: 61%)
of the title compound (IIb-2).
Yellow oil.
IR (NaCl, cm.sup.-1): 3304, 2924, 2856, 1464, 1374, 1120, 1076.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.75-0.96(m,6H),
1.00-1.65(m,29H), 3.05-4.25(m,20H), 4.95-5.08 (m,1H).
Preparation Example 22:
Preparation of monosodium
2-(2-hydroxy-3-tetradecyloxypropylamino)ethyl phosphate [Monosodium
(IIa-14)]: ##STR100##
A 300-ml flask equipped with a stirrer was charged with 5.13 g
(14.8 mmol) of 3-(2-hydroxyethylamino)-1-tetradecyloxy-2-propanol
prepared from tetradecyl glycidyl ether and ethanolamine in the
same manner as in Preparation Example 14, and 70 mol of
tetrahydrofuran, 1.95 g (16.9 mmol) of 85% phosphoric acid and 3.54
g (30.7 mmol) of P.sub.2 O.sub.5 were added thereto. The resultant
mixture was stirred at 65.degree. C. for 10 hours. After cooling
the mixture to room temperature, 0.56 g of water was added to the
mixture, stirring was conducted for 30 minutes, 5.0 g of 48%
aqueous NaOH were added further. After concentrating the resultant
reaction mixture under reduced pressure, the resultant residue was
subjected to extraction with ethanol by means of a Soxhlet's
extractor. The resultant extract was concentrated under reduced
pressure, and the residue was purified by column chromatography on
silica gel, thereby obtaining 2.32 g (yield: 34.9%) of the title
compound monosodium (IIa-14).
Colorless solid.
IR (KBr, cm.sup.-1): 3408, 2924, 2860, 1652, 1470, 1116, 978.
.sup.1 H-NMR (D.sub.2 O, .delta.): 0.80-1.10(m,3H),
1.26-1.95(m,24H), 3.02-4.64(m,11H).
Preparation Example 23:
Preparation of
3-[N-methyl-N-(2-phosphoryloxyethyl)amino]-1-tetradecyloxy-2-propyl
phosphate (IIa-15): ##STR101##
While stirring at -20.degree. C., a chloroform solution of 2.94 g
(8.52 mmol) of
3-[N-methyl-N-(2-hydroxyethyl)amino]-1-tetradecyloxy-2-propanol
prepared from tetradecyl glycidyl ether and N-methyl-ethanolamine
in the same manner as in Preparation Example 14 was added dropwise
over 5 minutes to a solution of 1.46 g (9.52 mmol) of POCl.sub.2
and 2.20 g (25.6 mmol) of pyridine in 30 ml of chloroform, which
had been charged into a 100-ml flask equipped with a stirrer. The
stirring was conducted further 30 minutes at -20.degree. C., and 20
ml of water was added, followed by extraction with chloroform. The
thus-obtained chloroform solution was concentrated under reduced
pressure, and the residue was purified by column chromatography on
silica gel, thereby obtaining 2.88 g (yield: 66.9%) of the title
compound (IIa-15).
Colorless solid.
IR (KBr, cm.sup.-1): 3464, 2924, 2852, 1462, 1072.
.sup.1 H-NMR (CDCl.sub.3 ; CD.sub.3 OD, .delta.): 0.82-1.03(m,3H),
1.06-1.75(m,24H), 2.20-3.04(m,11H), 3.18-4.62(m,7H).
Preparation Example 24:
Preparation of
N-(2-hydroxyethyl)-N,N-dimethyl-N-(3-(methoxy-2-hydroxypropyl)ammonium
iodide (IIb-3): ##STR102##
N-(3-Methoxy-2-hydroxypropyl)-N-methyl-2-hydroxyethylamine
represented by the following formula was first prepared.
##STR103##
A 100-ml two-necked flask equipped with a reflux condenser and
stirrer was charged with 8.8 g (0.1 mol) of methyl glycidyl ether,
9.0 g (0.12 mol) of 2-(methylamino)ethanol and 1.8 g of ethanol,
and the contents were heated and stirred at 80.degree. C. for 3
hours in a nitrogen atmosphere. After completion of the reaction,
distillation was conducted, thereby obtaining 14.5 g (yield: 89%)
of the above-mentioned compound.
Colorless oil.
IR (NaCl, cm.sup.-1): 3396, 2892, 1448, 1324, 1192, 1030, 874.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.33(s,3H), 2.37-2.72(m,4H),
3.32-3.47(m,2H), 3.39(s,3H), 3.64(t,2H,J=5.2 Hz),
3.84-3.96(m,1H).
A 100-ml flask equipped with a stirrer was then charged with 1.00 g
(6.13 mmol) of
N-(3-methoxy-2-hydroxypropyl)-N-methyl-2-hydroxyethylamine obtained
above and 10 ml of diethyl ether, and 0.45 ml of methyl iodide was
added, followed by stirring for 10 hours. After the resultant
reaction mixture was concentrated under reduced pressure, the
resultant residue was purified by column chromatography on silica
gel, thereby obtaining 1.31 g (yield: 70%) of the title compound
(IIb-3).
Yellow oil.
IR (NaCl, cm.sup.-1): 3368, 2932, 2896, 1480, 1114, 972.
.sup.1 H-NMR (D.sub.2 O, .delta.): 3.26(s,6H), 3.41(s,3H),
3.46-3.75(m,6H), 4.00-4.15(m,2H), 4.35-4.55(m,1H).
Preparation Example 25:
Preparation of
N-(2-hydroxypropyl)-N,N-dimethyl-N-[3-(12-hydroxyoctadecyl)-2-hydroxypropy
l]ammonium bromide (IIb-4): ##STR104##
1-[N-Methyl-N-(2-hydroxyethyl)amino]-3-(12-hydroxyoctadecyl)-2-propanol
was first prepared from 12-hydroxyoctadecyl glycidyl ether and
N-methylethanolamine in the same manner as in the preparation of
N-(3-methoxy-2-hydroxy-propyl)-N-methyl-2-hydroxyethylamine in
Preparation Example 24. A 200-ml autoclave was charged with 6.3 g
(15 mmol) of the thus-prepared compound, 100 ml of diethyl ether
and 14.2 g of methyl bromide, and the resultant mixture was stirred
at 48.degree. C. for 8 hours. The reaction mixture was then
concentrated under reduced pressure, and the resultant residue was
dissolved in methanol. Diethyl ether was added to the solution to
form crystals. The crystals were collected by filtration, thereby
obtaining 6.9 g (yield: 90%) of the title compound (IIb-4).
Colorless crystals.
IR (KBr, cm.sup.-1): 3320, 2920, 2852, 1470, 1122, 598.
.sup.1 H-NMR (CD.sub.3 OD, .delta.): 0.90(t,3H,J=6.5 Hz),
1.20-1.58(m,30H), 3.25(s,6H), 3.33-4.29(m,12H).
Example 43
Inhibitory effect of the amine derivatives on DNA synthesis of
epidermic keratinocyte:
a) Culture of human epidermic keratinocyte:
Human normal keratinocytes (trade name: Epipack) commercially
available from Kurabo Industries Ltd. were purchased and used as
keratinocytes. Incidentally, a medium for human normal
keratinocytes (trade name: K-GM) commercially available from the
said firm was used in the maintenance and subculture of the
cells.
b) Determination of DNA synthesis (thymidine incorporation):
Keratinocytes cultured in a vegetative state in a 24-well plate
were used. A medium in each well was first removed by suction to
add 450 .mu.l of K-GM, to which no pituitary gland extract was
added, to the well, thereby making a medium exchange. Thereafter,
each of the amine derivatives (shown in Table 1) obtained in the
above Preparation Examples was added thereto. Further, 0.2
.mu.Ci/ml of [.sup.3 H] thymidine was subsequently added to
incubate the culture for 4 hours. After the supernatant was then
removed by suction, and the well was washed 3 times with PBS(-),
500 .mu.l of 2N NaOH were added. After the culture was incubated at
37.degree. C. for 10 minutes, an equiamount of 2N HCl was added to
neutralize the culture, and 4 ml of 10% trichloroacetic acid
chilled with ice water were added, followed by leaving at rest for
30 minutes.
Precipitate was collected on a glass filter and then washed 3 times
with 3 ml of 10% trichloroacetic acid chilled with ice water. The
glass filter was washed further once with 3 ml of ethanol chilled
with ice water and then air-dried to measure its radioactivity by a
liquid scintillation counter, thereby calculating the thymidine
incorporation into the cells. The results are shown collectively in
Table 10.
TABLE 10 ______________________________________ Relative amount of
[.sup.3 H] thy- midine incorporated (%)* Amine derivative 10 .mu.M
100 .mu.M ______________________________________ (IIa-1) 73.0 21.2
(IIa-2) 14.0 2.7 (IIa-3) 42.5 11.3 (IIa-4) 9.3 1.9 (IIa-5) 22.8
19.7 (IIa-6) 19.3 31.6 (IIa-7) 16.4 4.7 (IIa-8) 29.5 11.1 (IIa-9)
37.2 18.3 (IIa-10) 12.0 2.8 (IIa-11) hydrochloride 29.2 14.3
(IIa-12) hydrochloride 19.7 2.6 (IIa-13) 6.0 0.7 (IIb-1) 14.4 4.6
(IIb-2) 25.3 2.8 (IIa-14) 22.6 0.9 (IIa-15) 17.6 2.4 (IIb-3) 65.5
12.0 (IIb-4) 12.4 3.2 ______________________________________ *:
Indicating the relative value where a control is assumed to be
100%.
It was apparent from the results shown in Table 10 that the
thymidine incorporation is markedly reduced by the addition of the
amine derivatives, namely, that the DNA synthesis of the human
epidermic keratinocytes is inhibited. Besides, the human epidermic
keratinocytes treated under the same conditions as described above
were observed on the fourth day. As a result, it was found that
most of the cells turn insoluble membrane (cornified envelope),
i.e., become keratinized. It is understood from this fact that the
amine derivatives (IIa) and (IIb) according to the present
invention are active in facilitating the keratinization of
epidermis.
Example 44
Effect of the amine derivatives on the transglutaminase activity of
epidermic keratinocyte:
(1) Determination of transglutaminase activity:
Keratinocytes cultured in a vegetative state in a 6-well plate were
used. A medium in each well was removed by suction to add 2 ml of
K-GM, to which no pituitary gland extract was added, to the well,
thereby making a medium exchange. Thereafter, the amine derivative
(IIb-1) was added thereto. After 24 hours, each well was washed 3
times with PBS(-), and the cells were then separated and collected
by a rubber policeman. The thus-obtained cell suspension was
centrifuged at 2,500 rpm for 10 minutes to collect the sediment. To
this sediment, were added 200 .mu.l of a buffer (a) [10 mM Tris-HCl
buffer, 10 mM DTT, 0.5 mM EDTA; pH 7.4], followed by
ultrasonication twice for 1 minute. The thus-obtained suspension
was centrifuged at 25,000 rpm for 30 minutes to obtain a
supernatant. This supernatant was divided into equiamount portions.
To each of the portions, was added a reaction solution [a solution
obtained by mixing 300 mM Tris-HCl buffer, pH 8.1; 100 .mu.l of 60
mM CaCl.sub.2 ; 100 .mu.l of 30 mM DTT; 100 .mu.l of distilled
water containing 540 .mu.g of dimethylcasein; 50 .mu.l of 12 mM
putrescine; 50 .mu.l of 2.5 .mu.Ci [.sup.14 C] putrescine; and 100
.mu.l of distilled water]. The thus-obtained mixture was incubated
at 37.degree. C. for 1 hour. After 600 .mu.l of 10% trichloroacetic
acid were then added to the mixture, and the resultant mixture was
left at rest for 30 minutes, precipitate was collected on a
nitrocellulose membrane of 0.45 .mu.m. After this membrane was
washed with 15 ml of 5% trichloroacetic acid (containing 1% of
putrescine) chilled with ice water, the radioactivity of the
precipitate on the membrane was determined by a liquid
scintillation counter.
(2) Result:
The value (dpm) of transglutaminase activity where the amine
derivative (IIb-1) has been added in an amount of 10 .mu.M is shown
in Table 11.
TABLE 11 ______________________________________ Transglutaminase
activity value (dpm) ______________________________________ Control
731.3 Amine derivative 3629.9 (IIb-1)
______________________________________
It is understood from the results shown in Table 11 that the amine
derivatives (IIa) and (IIb) have an effect of markedly enhancing
the transglutaminase activity of epidermic keratinocytes.
Example 45
Effect of the amine derivatives on wrinkles formed on hairless mice
by exposure to UVB:
Hairless mice (HR/ICR, aged 9 weeks at the beginning of the
experiment) were each exposed to UVB 3 times a week by using 6
Toshiba healthy lamps, 20SE. The amount of energy was measured by
means of a UV-Radiometer UVR-305/365D manufactured by TOKYO OPTICAL
K.K. The dose upon one exposure was determined to be 1 MED or less,
i.e., 65 mj in an amount of energy of 0.28 mM/cm.sup.2. The
exposure was effected for 20 weeks. After confirming the fact that
the mice had got wrinkles at their backs, they were divided into
groups each consisting of 8 mice. Ethanol solutions separately
containing the amine derivatives (shown in Table 12) in a
concentration of 0.025% were applied 5 times a week to their
corresponding groups of mice for 6 weeks in a dose of 80 .mu.l . As
a control, ethanol alone was applied in a dose of 80 .mu.l like the
samples.
After completion of the application, the degree of wrinkles was
visually observed to rank the samples in accordance with the
following standard (wrinkle index). The results are shown in Table
12.
(Wrinkle index; evaluation standard)
1: Wrinkles were completely removed;
2: Wrinkles were scarcely observed;
3: Wrinkles were somewhat observed;
4: Wrinkles were observed to a great extent.
In order to further analyze the particulars of wrinkles, skin
replicas of the size of 1 cm.sup.2 in diameter were gathered from 3
portions of the back in each of the mice using a Hydrophilic
Exaflex hydrophilic vinylsilicone impression material. Each of
these replicas was held horizontally and illuminated at an angle of
30 degrees from the horizontal direction, thereby finding the
proportion of shadows of the wrinkles as an area percent by means
of an image analyzer. The results are shown collectively in Table
12.
TABLE 12 ______________________________________ Area percent by
Amine derivative Wrinkle index image analysis (%)
______________________________________ Control 3.75 .+-. 0.09 6.42
.+-. 0.63 (IIa-1) 2.89 .+-. 0.18 2.91 .+-. 0.28 (IIa-6) 2.95 .+-.
0.16 3.10 .+-. 0.30 (IIa-7) 3.20 .+-. 0.28 3.80 .+-. 0.41 (IIa-8)
3.07 .+-. 0.27 3.47 .+-. 0.33 (IIa-10) 3.24 .+-. 0.30 4.01 .+-.
0.41 (IIa-11) hydrochloride 3.25 .+-. 0.21 4.04 .+-. 0.39 (IIa-12)
hydrochloride 3.00 .+-. 0.19 3.26 .+-. 0.32 (IIa-13) 3.25 .+-. 0.25
4.04 .+-. 0.41 (IIb-1) 3.40 .+-. 0.10 4.51 .+-. 0.42 (IIb-2) 3.33
.+-. 0.25 4.29 .+-. 0.44 Mono Na (IIa-14) 3.19 .+-. 0.25 3.85 .+-.
0.33 (IIa-15) 3.15 .+-. 0.20 3.73 .+-. 0.34 (IIb-3) 3.38 .+-. 0.20
4.32 .+-. 0.50 (IIb-4) 3.41 .+-. 0.15 4.48 .+-. 0.40
______________________________________
As apparent from the result shown in Table 12, the wrinkles formed
on the backs of the hairless mice can be removed by applying the
amine derivatives thereto.
Example 46
A W/O type cream having the following composition was obtained in
accordance with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Amine derivative (IIa-1)
0.08 (2) Cholesterol 0.5 (3) Cholesteryl isostearate 1.0 (4)
Polyether-modified silicone 1.5 (5) Cyclic silicone 20.0 (6)
Methylphenylpolysiloxane 2.0 (7) Methylpolysiloxane 2.0 (8)
Magnesium sulfate 0.5 (9) 55% Ethanol 5.0 (10) Carboxymethylchithin
(Chithin Liquid 0.5 HV, product of Ichimaru Pharcos Co., Ltd.) (11)
Purified water Balance ______________________________________
(Preparation process)
Components (1)-(7) were heated to 80.degree. C. to melt them, and
the components (8)-(11) were added to the melt. The resultant
mixture was intimately mixed to prepare a W/O type cream.
Example 47
An O/W type cream having the following composition was obtained in
accordance with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Polyoxyethylene (10)
hardened castor oil 1.0 (2) Sorbitan monostearate 0.5 (3) Sodium
stearoylmethyltaurine 0.5 (4) Cetostearyl alcohol 2.0 (5) Stearic
acid 1.8 (6) Amine derivative (IIa-4) 0.001 (7) Cholesterol 1.5 (8)
Cholesteryl isostearate 1.0 (9) Neopentyl glycol dicaprate 8.0 (10)
Methylpolysiloxane 5.0 (11) Glycerol 5.0 (12) Purified water
Balance ______________________________________
(Preparation process)
Components (1)-(10) were heated to 80.degree. C. to melt them, and
the components (11)-(12) were added to the melt. The resultant
mixture was intimately mixed to prepare an O/W type cream.
Example 48
A moisturizing sunscreen cream having the following composition was
obtained in accordance with the below-described preparation
process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Amine derivative
(IIa-15) 0.0005 (2) Silicon-coated zinc oxide 7.0 (3) 2-Ethylhexyl
p-methoxycinnamate 3.0 (4) Cholesteryl isostearate 1.0 (5)
Polyether-modified silicone 2.0 (6) Methylpolysiloxane 5.0 (7)
Cyclic silicone 15.0 (8) Magnesium sulfate 1.0 (9) Glycerol 5.0
(10) Purified water Balance
______________________________________
(Preparation process)
Components (1)-(7) were heated to 80.degree. C. to melt them, and
the components (8)-(10) were added to the melt. The resultant
mixture was intimately mixed to prepare a moisturizing sunscreen
cream.
Example 49
A pack having the following composition was obtained in accordance
with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Amine derivative
(IIa-11) hydrochloride 0.05 (2) Polyvinyl alcohol 15.0 (3) Sodium
carboxymethylcellulose 5.0 (4) Propylene glycol 3.0 (5) Ethanol 8.0
(6) Purified water Balance (7) Perfume base 0.5 (8) Antiseptic,
oxidizing agent q.s. ______________________________________
(Preparation process)
Components (1)-(8) were heated to 70.degree. C. to melt them, and
then cooled, thereby preparing a pack.
Example 50
An ointment having the following composition was obtained in
accordance with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Amine derivative (IIb-1)
0.005 (2) White petrolatum Balance (3) Cholesteryl isostearate 3.0
(4) Liquid paraffin 10.0 (5) Glyceryl ether 1.0 (6) Glycerol 10.0
______________________________________
(Preparation process)
Components (1)-(6) were heated to 80.degree. C. to melt them, and
then cooled, thereby preparing an ointment.
The dermatologic preparations according to the present invention,
which were prepared in Examples 46-50, had excellent effects of
preventing the occurrence of wrinkles and smoothing or removing
wrinkles and moreover inhibited parakeratosis, epidermic
hypertrophy and metabolic aberration of lipid and were excellent in
recovery of normal functions and maintenance of homeostasis.
Preparation Example 26:
Preparation of 1-(2-hydroxyethylamino)-2-octadecanol (IIc-1):
##STR105##
A 300-ml flask equipped with a stirrer and a dropping funnel was
charged with 45.8 g (0.75 mol) of ethanolamine and 9 g of ethanol.
While stirring the mixture at 80.degree. C., 13.4 g (50 mmol) of
1,2-epoxyoctadecane were added dropwise over 2 hours. Water was
added to the resultant reaction mixture, and white crystals formed
were collected by filtration, washed with water and then
recrystallized from methanol, thereby obtaining 12.3 g (yield:
74.6%) of the title compound (IIc-1).
Colorless solid.
Melting point: 84.5.degree.-86.0.degree. C.
IR (KBr, cm.sup.-1): 3400, 2920, 2852, 1472, 1126, 1076.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.82-0.96(m,3H),
1.14-1.51(m,31H), 2.42-2.88(m,7H), 3.69(t,J=4.8 Hz,2H).
Preparation Example 27:
Preparation of 1-[N-(2-hydroxyethyl)-N-methylamino)-2-octadecanol
(IIc-2): ##STR106##
A 300-ml flask equipped with a stirrer was charged with 26.85 g
(0.1 mol) of 1,2-epoxyoctadecane, 7.51 g (0.1 mol) of
N-methylethanolamine and 50 ml of ethanol, and the contents were
stirred at 80.degree. C. for 18 hours. After the solvent was
distilled off under reduced pressure, the resultant residue was
purified by column chromatography on silica gel, thereby obtaining
23.0 g (yield: 67%) of the title compound (IIc-2).
Colorless solid.
Melting point: 39.0.degree.-40.6.degree. C.
IR (NaCl, cm.sup.-1): 3392, 2920, 2852, 1660, 1466, 1300, 1080,
1042, 874.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.82-0.96(m,3H),
1.12-1.55(m,30H),
2.33(s,3H), 2.34-2.77(m,6H), 3.55-3.84(m,3H).
Preparation Example 28:
Preparation of
2-(2-hydroxyethylamino)-3,7,11,15-tetramethyl-1,3-hexadecanediol
(IIc-3): ##STR107##
A 100-ml two-necked flask equipped with a stirrer and a dropping
funnel was charged with 8.79 g (0.14 mol) of ethanolamine and 20.0
g of ethanol. While heating and stirring the mixture at 80.degree.
C. in a nitrogen atmosphere, 3.01 g (9.6 mmol) of
2,3-epoxy-3,7,11,15-tetramethyl-1,3-hexadecanediol were added
dropwise over 1 hour. After heating and stirring the mixture
further for 2 hours, the resultant reaction mixture was
concentrated under reduced pressure, and the resultant residue was
purified by column chromatography on silica gel, thereby obtaining
3.02 g (yield: 84%) of the title compound (IIc-3).
Yellow solid.
Melting point: 49.1.degree.-50.2.degree. C.
IR (KBr, cm.sup.-1): 3388, 3276, 2920, 2852, 1464, 1380, 1058,
1034.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.80-0.95(m,15H),
0.98-1.68(m,21H), 2.44(t,J=4.3 Hz,1H), 2.72-3.08(m,6H),
3.58-3.66(m,4H).
Preparation Example 29:
Preparation of
3-(2-hydroxyethylamino)-4-tetradecyloxy-2-methyl-2-butanol (IIc-4):
##STR108##
A 100-ml two-necked flask equipped with a stirrer and a dropping
funnel was charged with 15.3 g (16.7 mmol) of ethanolamine and 5.0
g of ethanol. While heating and stirring the mixture at 80.degree.
C. in a nitrogen atmosphere, an ethanol solution of 5.00 g (16.7
mmol) of 1-tetradecyloxy-3-methyl-2-butene oxide was added dropwise
over 3 hours. After heating and stirring the mixture further for 16
hours, the resultant reaction mixture was concentrated under
reduced pressure, and the resultant residue was purified by column
chromatography on silica gel, thereby obtaining 3.47 g (yield: 58%)
of the title compound (IIc-4).
Pale yellow oil.
IR (NaCl, cm.sup.-1): 3384, 2924, 2852, 1462, 1374, 1114, 1060.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.88(t,J=6.4 Hz,3H),
1.06-1.72(m,30H), 2.55(dd,J=4.1 Hz,6.4 Hz,1H), 2.63-3.05(m,5H),
3.30-3.80(m,6H).
Preparation Example 30:
A reaction was conducted in the same manner as in Preparation
Example 29 except that 1-tetradecyoxy-2-butene oxide was used in
place of 1-tetradecyloxy-3-methyl-2-butene oxide in Preparation
Example 29, thereby preparing the following amine derivative
(IIc-5). ##STR109##
Pale yellow solid.
Melting point: 54.4.degree.-55.4.degree. C.
IR (KBr, cm.sup.-1): 3280, 2920, 2852, 1468, 1374, 1116, 1060.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.88(t,J=6.4 Hz,3H),
1.08-1.68(m,27H), 2.41(brs,3H), 2.65(ddd,J=6.2 Hz,4.1 Hz,4.1
Hz,1H), 2.83(t,J=2.3 Hz,2H), 3.30-3.78(m,6H), 3.90(dq,J=3.9 Hz,6.2
Hz,1H).
Preparation Example 31:
Preparation of 2-(9-octadecenylamino)-1-ethanol (IIc-6):
##STR110##
A 100-ml eggplant type flask equipped with a stirrer was charged
with 1.40 g (37.2 mmol) of LiAlH.sub.4 and 30 ml of
tetrahydrofuran. While heating and stirring the contents at room
temperature in an N.sub.2 atmosphere, a tetrahydrofuran solution of
1.67 g (5.12 mmol) of N-(9-octadecenoyl)ethanolamine was added
dropwise over 10 minutes. After the mixture was heated to
60.degree. C. and stirred for 16 hours, the resultant reaction
mixture was cooled to room temperature, and 14 g of 5% aqueous KOH.
After a salt deposited was separated by filtration, the filtrate
was concentrated under reduced pressure, and the resultant residue
was purified by column chromatography on silica gel, thereby
obtaining 0.96 g (yield: 65%) of the title compound (IIc-6).
Pale yellow oil.
IR (NaCl, cm.sup.-1): 3328, 2920, 2852, 1458, 1376, 1118, 1060.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.88(t,J=6.6 Hz,3H),
1.15-1.65(m,24H), 1.88-2.15(m,4H), 2.35(brs,2H), 2.61(t,J=7.3
Hz,2H), 2.76(t,J=5.3 Hz,2H), 3.64(t,J=5.3 Hz,2H),
5.22-5.48(m,5H).
Preparation Examples 32-33:
Reactions were conducted in the same manner as in Preparation
Example 31 except that N-octadecanoylethanolamine and
N-methyl-branched isostearoylethanolamine were respectively used in
place of N-(9-octadecenoyl)ethanolamine in Preparation Example 31,
thereby synthesizing the following amine derivatives (IIc-7) and
(IIc-8). ##STR111## (in the formula, .alpha. and .beta. denote
numbers satisfying the following relationship:
.alpha.+.beta.=11-17, .alpha.=4-10, .beta.=5-11, and having a
distribution that the peaks of .alpha. and .beta. are 7 and 8,
respectively.)
(IIc-7):
Colorless solid.
Melting point: 57.3.degree.-58.2.degree. C.
IR (KBr, cm.sup.-1): 3370, 2914, 2848, 1467, 1035.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.88(t,J=6.7 Hz,3H),
1.04-1.75(m,32H), 2.42(brs,2H), 2.61(t,J=7.3 Hz,2H), 2.77(t,J=5.1
Hz,2H), 3.65(t,J=5.1 Hz,2H).
(IIc-8):
Colorless oil.
IR (NaCl, cm.sup.-1): 3196, 2924, 2856, 1460, 1376, 1122, 1062.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.77-1.00(m,6H),
1.14-1.78(m,29H), 2.24-2.56(m,2H), 2.62(t,J=7.3 Hz,2H),
2.77(t,J=5.1 Hz,2H), 3.65(t,J=5.1 Hz,2H).
Preparation Example 34:
Preparation of monosodium
2-[N-(2-hydroxyoctadecyl)-N-methylamino]ethyl phosphate [Monosodium
(IIc-8)]: ##STR112##
A 200-ml flask equipped with a stirrer was charged with 5.10 g
(14.8 mmol) of the amine derivative (IIc-2) obtained in Preparation
Example 27, 50 mol of tetrahydrofuran and 3.54 g (30.7 mmol) of 85%
phosphoric acid, and the contents were stirred at 65.degree. C. for
7 hours. After allowing the mixture to cool, 0.56 g of water was
added to stir the mixture for 30 minutes. Then, 2.38 g of NaOH and
3 g of water were added to the mixture, and the resultant reaction
mixture was stirred for 30 minutes, followed by concentration under
reduced pressure. The resultant residue was subjected to extraction
with ethanol by means of a Soxhlet's extractor. After the solvent
was distilled off under reduced pressure, the resultant residue was
purified by column chromatography on silica gel, thereby obtaining
0.75 g (yield: 11%) of the title compound.
Colorless solid.
IR (KBr, cm.sup.-1): 3296, 2920, 2852, 1470, 1148, 1074, 938.
.sup.1 H-NMR (CD.sub.3 OD, .delta.): 0.78-0.98(m,3H),
1.04-1.87(m,30H), 2.82-3.68(m,7H), 3.75-4.32(m,3H).
Example 51
Effect of the amine derivatives on wrinkles formed on hairless mice
by exposure to UVB:
(1) Hairless mice (HR/ICR, aged 9 weeks at the beginning of the
experiment) were each exposed to UVB 3 times a week by using 6
Toshiba healthy lamps, 20SE. The amount of energy was measured by
means of a UV-Radiometer UVR-305/365D manufactured by TOKYO OPTICAL
K.K. The dose upon one exposure was determined to be 1 MED or less,
i.e., 65 mj in an amount of energy of 0.28 mM/cm.sup.2. The
exposure was effected for 20 weeks. After confirming the fact that
the mice had got wrinkles at their backs, they were divided into
groups each consisting of 8 mice. Ethanol solutions separately
containing the amine derivatives (IIc-1)-(IIc-8) in a concentration
of 0.025% were applied 5 times a week to their corresponding groups
of mice for 6 weeks in a dose of 80 .mu.l . As a control, ethanol
alone was applied in a dose of 80 .mu.l like the samples.
After completion of the application, the degree of wrinkles was
visually observed to rank the samples in accordance with the
following standard (wrinkle index). The results are shown in Table
13.
(Wrinkle index; evaluation standard)
1: Wrinkles were completely removed;
2: Wrinkles were scarcely observed;
3: Wrinkles were somewhat observed;
4: Wrinkles were observed to a great extent.
In order to further analyze the particulars of wrinkles, skin
replicas of the size of 1 cm.sup.2 in diameter were gathered from 3
portions of the back in each of the mice using a Hydrophilic
Exaflex hydrophilic vinylsilicone impression material. Each of
these replicas was held horizontally and illuminated at an angle of
30 degrees from the horizontal direction, thereby finding the
proportion of shadows of the wrinkles as an area percent by means
of an image analyzer. The results are shown collectively in Table
13.
TABLE 13 ______________________________________ Area percent by
Amine derivative Wrinkle index image analysis (%)
______________________________________ Control 3.75 .+-. 0.09 6.42
.+-. 0.63 (IIc-1) 3.60 .+-. 0.10 6.08 .+-. 0.51 (IIc-2) 3.20 .+-.
0.27 3.88 .+-. 0.35 (IIc-3) 3.45 .+-. 0.31 4.67 .+-. 0.41 (IIc-4)
3.13 .+-. 0.15 3.66 .+-. 0.32 (IIc-6) 3.00 .+-. 0.21 3.26 .+-. 0.30
(IIc-7) 2.90 .+-. 0.17 2.92 .+-. 0.25 Mono Na (IIc-8) 3.40 .+-.
0.12 4.51 .+-. 0.41 ______________________________________
As apparent from the result shown in Table 13, the wrinkles formed
on the backs of the hairless mice can be removed by applying the
amine derivatives (IIc-1)-(IIc-8) thereto.
Example 52
Inhibitory effect of the amine derivatives on DNA synthesis of
epidermic keratinocyte:
(1) Method:
a) Culture of human epidermic keratinocyte:
Human normal keratinocytes (trade name: Epipack) commercially
available from Kurabo Industries Ltd. were purchased and used as
keratinocytes. Incidentally, a medium for human normal
keratinocytes (trade name: K-GM) commercially available from the
said firm was used in the maintenance and subculture of the
cells.
b) Determination of DNA synthesis (thymidine incorporation):
Keratinocytes cultured in a vegetative state in a 24-well plate
were used. A medium in each well was first removed by suction to
add 450 .mu.l of K-GM, to which no pituitary gland extract was
added, to the well, thereby making a medium exchange. Thereafter,
each of the amine derivatives (IIc-1)-(IIc-8) obtained in the above
Preparation Examples was added thereto. Further, 0.2 .mu.Ci/ml of
[.sup.3 H] thymidine was subsequently added to incubate the culture
for 4 hours. After the supernatant was then removed by suction, and
the well was washed 3 times with PBS(-), 500 .mu.l of 2N NaOH were
added. After the culture was incubated at 37.degree. C. for 10
minutes, an equiamount of 2N HCl was added to neutralize the
culture, and 4 ml of 10% trichloroacetic acid chilled with ice
water were added, followed by leaving at rest for 30 minutes.
Precipitate was collected on a glass filter and then washed 3 times
with 3 ml of 10% trichloroacetic acid chilled with ice water. The
glass filter was washed further once with 3 ml of ethanol chilled
with ice water and then air-dried to measure its radioactivity by a
liquid scintillation counter, thereby calculating the thymidine
incorporation into the cells. The results are shown in Table
14.
TABLE 14 ______________________________________ Relative amount of
[.sup.3 H] thymidine incorporated (%)* Amine derivative 10 .mu.M
100 .mu.M ______________________________________ (IIc-1) 48.4 8.9
(IIc-2) 63.2 14.6 (IIc-3) 5.2 0.9 (IIc-4) 9.7 1.9 (IIc-5) 14.3 4.3
(IIc-6) 23.0 4.7 (IIc-7) 51.6 10.1 Mono Na (IIc-8) 6.7 2.9
______________________________________ *: Indicating the relative
value where a control is assumed to be 100%.
It was apparent from the results shown in Table 14 that the
thymidine incorporation is markedly reduced by the addition of the
amine derivatives, namely, that the DNA synthesis of the human
epidermic keratinocytes is inhibited. Besides, the human epidermic
keratinocytes treated under the same conditions as described above
were observed on the fourth day. As a result, it was found that
most of the cells lead to insoluble membrane (cornified envelope),
i.e., become keratinized. It is understood from this fact that the
amine derivatives according to the present invention are active in
facilitating the keratinization of epidermis.
Example 53
A W/O type cream having the following composition was obtained in
accordance with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Amine derivative (IIc-1)
0.01 (2) Cholesterol 0.5 (3) Cholesteryl isostearate 1.0 (4)
Polyether-modified silicone 1.5 (5) Cyclic silicone 20.0 (6)
Methylphenylpolysiloxane 2.0 (7) Methylpolysiloxane 2.0 (8)
Magnesium sulfate 0.5 (9) 55% Ethanol 5.0 (10) Carboxymethylchithin
(Chithin Liquid 0.5 HV, product of Ichimaru Pharcos Co., Ltd.) (11)
Purified water Balance ______________________________________
(Preparation process) Components (1)-(7) were heated to 80.degree.
C. to melt them, and the components (8)-(11) were added to the
melt. The resultant mixture was intimately mixed to prepare a W/O
type cream.
Example 54
An O/W type cream having the following composition was obtained in
accordance with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Polyoxyethylene (10)
hardened castor oil 1.0 (2) Sorbitan monostearate 0.5 (3) Sodium
stearoylmethyltaurine 0.5 (4) Cetostearyl alcohol 2.0 (5) Stearic
acid 1.8 (6) Amine derivative (IIc-5) 0.001 (7) Cholesterol 1.5 (8)
Cholesteryl isostearate 1.0 (9) Neopentyl glycol dicaprate 8.0 (10)
Methylpolysiloxane 5.0 (11) Glycerol 5.0 (12) Purified water
Balance ______________________________________
(Preparation process)
Components (1)-(10) were heated to 80.degree. C. to melt them, and
the components (11)-(12) were added to the melt. The resultant
mixture was intimately mixed to prepare an O/W type cream.
Example 55
A moisturizing sunscreen cream having the following composition was
obtained in accordance with the below-described preparation
process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Amine derivative (IIc-4)
0.05 (2) Silicon-coated zinc oxide 7.0 (3) 2-Ethylhexyl
p-methoxycinnamate 3.0 (4) Cholesteryl isostearate 1.0 (5)
Polyether-modified silicone 2.0 (6) Methylpolysiloxane 5.0 (7)
Cyclic silicone 15.0 (8) Magnesium sulfate 1.0 (9) Glycerol 5.0
(10) Purified water Balance
______________________________________
(Preparation process)
Components (1)-(7) were heated to 80.degree. C. to melt them, and
the components (8)-(10) were added to the melt. The resultant
mixture was intimately mixed to prepare a moisturizing sunscreen
cream.
Example 56
A pack having the following composition was obtained in accordance
with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Monosodium amine
derivative (IIc-8) 0.05 (2) Polyvinyl alcohol 15.0 (3) Sodium
carboxymethylcellulose 5.0 (4) Propylene glycol 3.0 (5) Ethanol 8.0
(6) Purified water Balance (7) Perfume base 0.5 (8) Antiseptic,
oxidizing agent q.s. ______________________________________
(Preparation process)
Components (1)-(8) were heated to 70.degree. C. to melt them, and
then cooled, thereby preparing a pack.
Example 57
An ointment having the following composition was obtained in
accordance with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Amine derivative (IIc-6)
0.075 (2) White petrolatum Balance (3) Cholesteryl isostearate 3.0
(4) Liquid paraffin 10.0 (5) Glyceryl ether 1.0 (6) Glycerol 10.0
______________________________________
(Preparation process)
Components (1)-(6) were heated to 80.degree. C. to melt them, and
then cooled, thereby preparing an ointment.
The dermatologic preparations according to the present invention,
which were prepared in Examples 53-57, had excellent effects of
preventing the occurrence of wrinkles and smoothing or removing
wrinkles and moreover inhibited parakeratosis, epidermic
hypertrophy and metabolic aberration of lipid and were excellent in
recovery of normal functions and maintenance of homeostasis.
Preparation Example 35:
Preparation of 1-(2-hydroxyethylamino)-2,16-hexadecanediol (IId-1):
##STR113##
A 300-ml three-necked flask equipped with a stirrer, dropping
funnel and N.sub.2 inlet tube was charged with 40 ml of dimethyl
sulfoxide and 1.2 g (30 mmol) of 60% sodium hydride. The contents
were stirred at 75.degree. C. for 1.5 hours in an N.sub.2
atmosphere and then cooled to room temperature. To this mixture, a
solution of 8.93 g (25 mmol) of methyltriphenylphosphonium bromide
in 40 ml of dimethyl sulfoxide was added dropwise over 10 minutes.
The resultant mixture was stirred further for 20 minutes at room
temperature. To this mixture, a solution of 3.27 g (10 mmol) of
15-(2-tetrahydropyranyloxy)pentadecanal in 15 ml of THF was added
dropwise over 5 minutes, followed by stirring further for 30
minutes. After completion of the reaction, the reaction mixture was
added with water and subjected to extraction with hexane, followed
by concentration under reduced pressure. Thereafter, the resultant
residue was purified by flash column chromatography on silica gel,
thereby obtaining 1.49 g (yield: 46%) of
1-(2-tetrahydropyranyloxy)-15-hexadecene.
A 500-ml flask equipped with a stirrer was charged with 1.49 g (4.6
mmol) of 1-(2-tetrahydropyranyloxy)-15-hexadecene, 70 ml of THF, 70
ml of methanol and 19 mg (0.1 mmol) of p-toluenesulfonic acid, and
the contents were stirred at 40.degree. C. for 12 hours. After
completion of the reaction, the reaction mixture was concentrated
under reduced pressure. The resultant residue was added with a 5%
aqueous solution of NaHCO.sub.3 and subjected to extraction with
chloroform, and the solvent was distilled off under reduced
pressure.
A 500-ml flask equipped with a stirrer and N.sub.2 inlet tube was
charged with this residue, 60 ml of dichloromethane and 2.64 g
(15.3 mmol) of m-chloroperbenzoic acid, and the contents were
stirred at room temperature for 3 days. After completion of the
reaction, the reaction mixture was added with a 5% aqueous solution
of NaHCO.sub.3 and subjected to extraction with chloroform, the
solvent was distilled off under reduced pressure, and the residue
was then purified by chromatography on silica gel, thereby
obtaining 0.89 g (yield: 76%) of 1,2-epoxy-16-hexadecanol.
A 50-ml two-necked flask equipped with a stirrer, dropping funnel
and N.sub.2 inlet tube was charged with 4.14 g (68 mmol) of
ethanolamine and 0.8 g of ethanol. While heating and stirring the
mixture at 80.degree. C. in an N.sub.2 atmosphere, an ethanol
solution of 0.87 g (3.4 mmol) of 1,2-epoxy-16-hexadecanol was added
dropwise over 1.5 hours. The resultant mixture was stirred further
for 2 hours at 80.degree. C. After completion of the reaction,
ethanol and excess ethanolamine were distilled off under reduced
pressure, and the resultant residue was purified by flash column
chromatography on silica gel, thereby obtaining 0.72 g (yield: 68%)
of the title compound (IId-1).
Colorless powder.
Melting point: 102.8.degree. C.
IR (KBr, cm.sup.-1): 3364, 2920, 2852, 1464, 1350, 1120, 1056.
.sup.1 H-NMR (CD.sub.3 OD, .delta.): 1.16-1.64(m,26H),
2.47-2.86(m,4H), 3.37-3.77(m,5H).
Preparation Example 36:
Preparation of
1-(2-hydroxyethylamino)-12-methyl-2,12-heneicosanediol (IId-2):
##STR114##
A 200-ml three-necked flask equipped with a stirrer, dropping
funnel and N.sub.2 inlet tube was charged with 1.22 g (50 mmol) of
Mg for a Grignard reagent and 50 ml of anhydrous tetrahydrofuran.
While stirring the contents at room temperature in an N.sub.2
atmosphere, 11.66 g (50 mmol) of 1-bromo-10-undecene were added
dropwise over 1 hour. After completion of the dropping, the
resultant mixture was stirred further for 1 hour at room
temperature. To this mixture, 8.52 g (50 mmol) of 2-undecanone were
added, followed by stirring at room temperature for 1 hour. The
resultant reaction mixture was added with an aqueous solution of
NH.sub.4 Cl and subjected to extraction with isopropyl ether, and
the resultant extract was concentrated under reduced pressure.
The thus-obtained residue was transferred to a 200-ml flask
equipped with a stirrer, to which 50 ml of dichloromethane and
12.18 g (60 mmol) of m-chloroperbenzoic acid were added. The
contents were stirred at room temperature for 48 hours. Solids
deposited were separated by filtration, and the resultant filtrate
was concentrated under reduced pressure, and the residue was
purified by chromatography on silica gel, thereby obtaining 10.16 g
(yield: 59.7%) of 20,21-epoxy-9-methyl-9-heneicosanol.
A 50-ml two-necked flask equipped with a stirrer, dropping funnel
and N.sub.2 inlet tube was charged with 18.3 g (300 mmol) of
ethanolamine and 3.8 g of ethanol. While heating and stirring the
mixture at 80.degree. C. in an N.sub.2 atmosphere, 5.11 g (15 mmol)
of 20,21-epoxy-9-methyl-9-heneicosanol were added dropwise over 1.5
hours. After completion of the dropping, ethanol and excess
ethanolamine were distilled off under reduced pressure, and the
resultant residue was purified by flash column chromatography on
silica gel, thereby obtaining 4.52 g (yield: 75%) of the title
compound (IId-2).
Pale yellow oil.
IR (NaCl, cm.sup.-1): 3352, 2928, 2856, 1458, 1372, 1130, 1048,
748.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.88(t,J=6.5 Hz,3H),
1.14(s,3H), 1.01-1.78(m,34H), 2.45-3.30(m,8H), 3.53-3.80(m,3H).
Preparation Example 37:
Preparation of 16-[N,N-bis(2-hydroxyethyl)amino]-1-hexadecanol
(IId-3): ##STR115##
A 200-ml flask equipped with a stirrer was charged with 16.6 g (158
mmol) of diethanolamine and 20.1 g (79 mmol) of
cyclohexadecanolide, to which 0.21 g (3.9 mmol) of sodium methoxide
was added. The contents were stirred at 80.degree. C. for 18 hours.
After completion of the reaction, water was added, and solids
deposited were collected by filtration and recrystallized from
methanol, thereby obtaining 23.3 g (yield: 82%) of
N,N-bis(2-hydroxyethyl)-16-hydroxyhexadecanamide.
A 500-ml flask equipped with a stirrer and reflux condenser was
charged with 3.01 g (79.3 mmol) of LiAlH.sub.4 and 200 ml of
tetrahydrofuran. While stirring the mixture at room temperature in
an N.sub.2 atmosphere, 5.00 g (13.9 mmol) of
N,N-bis(2-hydroxyethyl)-16-hydroxyhexadecanamide were added,
followed by stirring at 65.degree. C. for 18 hours. After cooling
the reaction mixture to room temperature, 15 g of 3% aqueous KOH
were added, and a salt deposited was separated by filtration. The
solvent was then distilled off under reduced pressure, and the
resultant residue was purified by column chromatography on silica
gel, thereby obtaining 2.98 g (yield: 62%) of the title compound
(IId-3).
Colorless solid.
Melting point: 67.6.degree.-68.8.degree. C.
IR (KBr, cm.sup.-1): 3332, 2920, 2852, 1470, 1038. .sup.1 H-NMR
(CDCl.sub.3, .delta.): 1.15-1.68(m,31H), 2.52(t,J=7.6 Hz,2H),
2.66(t,J=5.2 Hz,4H), 3.54-3.68(m,6H).
Preparation Example 38:
Preparation of
16-(2-hydroxyethylamino)-1-(2-tetrahydropyranyloxy)hexadecane
(IId-4): ##STR116##
A reaction was conducted in the same manner as in Preparation
Example 37 except that ethanolamine and methyl
16-(2-tetrahydropyranyloxy)hexadecanate were used in place of
diethanolamine and cyclohexadecanolide, respectively, in
Preparation Example 37, thereby obtaining the title compound
(IId-4).
Colorless solid.
IR (KBr, cm.sup.-1): 3276, 2920, 2852, 1474, 1368, 1116, 1064,
1032.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.90-1.98(m,34H), 2.10(brs,2H),
2.61(t,J=7.2 Hz,2H), 2.76(t,J=5.1 Hz,2H), 3.25-3.98(m,6H),
4.52-4.65(m, 1H).
Preparation Example 39:
Preparation of 16-(2-hydroxyethylamino)-1-hexadecanol (IId-5):
A 200-ml flask equipped with a stirrer was charged with 4.82 g
(12.5 mmol) of the amine derivative (IId-4) obtained in Preparation
Example 38 and 100 ml of methanol, to which 1.45 ml (17.4 mmol) of
12N hydrochloric acid were added. The resultant mixture was stirred
at 40.degree. C. for 30 minutes. Then, 1.88 g (22.5 mmol) of 48%
aqueous NaOH were added, followed by stirring at room temperature
for 1 hour. The reaction mixture was concentrated under reduced
pressure, and water was then added. Crystals thus deposited were
collected by filtration and recrystallized from methanol, thereby
obtaining 2.64 g (yield: 74%) of the title compound (IId-5).
Colorless solid.
Melting point: 80.0.degree.-81.2.degree. C.
IR (KBr, cm.sup.-1): 3372, 2920, 2848, 1470, 1110, 1058.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.15-1.65(m,28H), 1.88(brs,3H),
2.62(t,J=7.0 Hz,2H), 2.76(t,J=5.2 Hz,2H), 3.54-3.68(m,4H).
Example 58
Inhibitory effect of the amine derivatives on DNA synthesis of
epidermic keratinocyte:
(1) Method:
a) Culture of human epidermic keratinocyte:
Human normal keratinocytes (trade name: Epipack) commercially
available from Kurabo Industries Ltd. were purchased and used as
keratinocytes. Incidentally, a medium for human normal
keratinocytes (trade name: K-GM) commercially available from the
said firm was used in the maintenance and subculture of the
cells.
b) Determination of DNA synthesis (thymidine incorporation):
Keratinocytes cultured in a vegetative state in a 24-well plate
were used. A medium in each well was first removed by suction to
add 450 .mu.l of K-GM, to which no pituitary gland extract was
added, to the well, thereby making a medium exchange. Thereafter,
each of the amine derivatives (IId-1)-(IId-5) obtained in the above
Preparation Examples was added thereto. Further, 0.2 .mu.Ci/ml of
[.sup.3 H] thymidine was subsequently added to incubate the culture
for 4 hours. After the supernatant was then removed by suction, and
the well was washed 3 times with PBS(-), 500 .mu.l of 2N NaOH were
added. After the culture was incubated at 37.degree. C. for 10
minutes, an equiamount of 2N HCl was added to neutralize the
culture, and 4 ml of 10% trichloroacetic acid chilled with ice
water were added, followed by leaving at rest for 30 minutes.
Precipitate was collected on a glass filter and then washed 3 times
with 3 ml of 10% trichloroacetic acid chilled with ice water. The
glass filter was washed further once with 3 ml of ethanol chilled
with ice water and then air-dried to measure its radioactivity by a
liquid scintillation counter, thereby calculating the thymidine
incorporation into the cells.
(2) Result:
The relative amounts of the [.sup.3 H] thymidine incorporated at
the time each of the amine derivatives (IId-1) to (IId-5) has been
added in amounts of 10 .mu.M and 100 .mu.M are shown in Table
1.
TABLE 15 ______________________________________ Relative amount of
[.sup.3 H] thymidine incorporated (%)* Amine derivative 10 .mu.M
100 .mu.M ______________________________________ (IId-1) 52.6 18.3
(IId-2) 9.1 0.7 (IId-3) 16.2 3.9 (IId-4) 41.5 10.2 (IId-5) 8.8 1.1
______________________________________ *: Indicating the relative
value where a control is assumed to be 100%.
It was apparent from Table 15 that the thymidine incorporation is
markedly reduced by the addition of the amine derivatives, namely,
that the DNA synthesis of the human epidermic keratinocytes is
inhibited. Besides, the human epidermic keratinocytes treated under
the same conditions as described above were observed on the fourth
day. As a result, it was found that most of the cells turn
insoluble membrane (cornified envelope), i.e., become keratinized.
It is understood from this fact that the amine derivatives
according to the present invention are active in facilitating the
keratinization of epidermis.
Example 59
Effect of the amine derivatives on wrinkles formed on hairless mice
by exposure to UVB:
(1) Hairless mice (HR/ICR, aged 9 weeks at the beginning of the
experiment) were each exposed to UVB 3 times a week by using 6
Toshiba healthy lamps, 20SE. The amount of energy was measured by
means of a UV-Radiometer UVR-305/365D manufactured by TOKYO OPTICAL
K.K. The dose upon one exposure was determined to be 1 MED or less,
i.e., 65 mj in an amount of energy of 0.28 mM/cm.sup.2. The
exposure was effected for 20 weeks. After confirming the fact that
the mice had got wrinkles at their backs, they were divided into
groups each consisting of 8 mice. Ethanol solutions separately
containing the amine derivatives (IId-1)-(IId-5) in a concentration
of 0.025% were applied 5 times a week to their corresponding groups
of mice for 6 weeks in a dose of 80 .mu.l. As a control, ethanol
alone was applied in a dose of 80 .mu.l like the samples.
After completion of the application, the degree of wrinkles was
visually observed to rank the samples in accordance with the
following standard (wrinkle index). The results are shown in Table
16.
(Wrinkle index)
1: Wrinkles were completely removed;
2: Wrinkles were scarcely observed;
3: Wrinkles were somewhat observed;
4: Wrinkles were observed to a great extent.
In order to further analyze the particulars of wrinkles, skin
replicas of the size of 1 cm.sup.2 in diameter were gathered from 3
portions of the back in each of the mice using a Hydrophilic
Exaflex hydrophilic vinylsilicone impression material. Each of
these replicas was held horizontally and illuminated at an angle of
30 degrees from the horizontal direction, thereby finding the
proportion of shadows of the wrinkles as an area percent by means
of an image analyzer. The results are shown collectively in Table
16.
TABLE 16 ______________________________________ Area percent by
Amine derivative Wrinkle index image analysis (%)
______________________________________ Control 3.75 .+-. 0.09 6.42
.+-. 0.63 (IId-1) 3.00 .+-. 0.43 3.26 .+-. 0.30 (IId-2) 3.21 .+-.
0.31 3.91 .+-. 0.41 (IId-3) 2.83 .+-. 0.42 2.72 .+-. 0.28 (IId-5)
2.50 .+-. 0.45 1.69 .+-. 0.18
______________________________________
As apparent from the result shown in Table 16, the wrinkles formed
on the backs of the hairless mice can be removed by applying the
amine derivatives (IId-1), (IId-2), (IId-3) and (IId-5)
thereto.
Example 60
A W/O type cream having the following composition was obtained in
accordance with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Amine derivative (IId-1)
0.1 (2) Cholesterol 0.5 (3) Cholesteryl isostearate 1.0 (4)
Polyether-modified silicone 1.5 (5) Cyclic silicone 20.0 (6)
Methylphenylpolysiloxane 2.0 (7) Methylpolysiloxane 2.0 (8)
Magnesium sulfate 0.5 (9) 55% Ethanol 5.0 (10) Carboxymethylchithin
(Chithin Liquid 0.5 HV, product of Ichimaru Pharcos Co., Ltd.) (11)
Purified water Balance ______________________________________
(Preparation process)
Components (1)-(7) were heated to 80.degree. C. to melt them, and
the components (8)-(11) were added to the melt. The resultant
mixture was intimately mixed to prepare a W/O type cream.
Example 61
An O/W type cream having the following composition was obtained in
accordance with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Polyoxyethylene (10)
hardened castor oil 1.0 (2) Sorbitan monostearate 0.5 (3) Sodium
stearoylmethyltaurine 0.5 (4) Cetostearyl alcohol 2.0 (5) Stearic
acid 1.8 (6) Amine derivative (IId-3) 0.001 (7) Cholesterol 1.5 (8)
Cholesteryl isostearate 1.0 (9) Neopentyl glycol dicaprate 8.0 (10)
Methylpolysiloxane 5.0 (11) Glycerol 5.0 (12) Purified water
Balance ______________________________________
(Preparation process)
Components (1)-(10) were heated to 80.degree. C. to melt them, and
the components (11)-(12) were added to the melt. The resultant
mixture was intimately mixed to prepare an O/W type cream.
Example 62
A moisturizing sunscreen cream having the following composition was
obtained in accordance with the below-described preparation
process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Amine derivative (IId-5)
0.05 (2) Silicon-coated zinc oxide 7.0 (3) 2-Ethylhexyl
p-methoxycinnamate 3.0 (4) Cholesteryl isostearate 1.0 (5)
Polyether-modified silicone 2.0 (6) Methylpolysiloxane 5.0 (7)
Cyclic silicone 15.0 (8) Magnesium sulfate 1.0 (9) Glycerol 5.0
(10) Purified water Balance
______________________________________
(Preparation process)
Components (1)-(7) were heated to 80.degree. C. to melt them, and
the components (8)-(10) were added to the melt. The resultant
mixture was intimately mixed to prepare a moisturizing sunscreen
cream.
Example 63
A pack having the following composition was obtained in accordance
with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Amine derivative (IId-3)
hydrochloride 0.05 (2) Polyvinyl alcohol 15.0 (3) Sodium
carboxymethylcellulose 5.0 (4) Propylene glycol 3.0 (5) Ethanol 8.0
(6) Purified water Balance (7) Perfume base 0.5 (8) Antiseptic,
oxidizing agent q.s. ______________________________________
(Preparation process)
Components (1)-(8) were heated to 70.degree. C. to melt them, and
then cooled, thereby preparing a pack.
Example 64
An ointment having the following composition was obtained in
accordance with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Amine derivative (IId-5)
0.2 (2) White petrolatum Balance (3) Cholesteryl isostearate 3.0
(4) Liquid paraffin 10.0 (5) Glyceryl ether 1.0 (6) Glycerol 10.0
______________________________________
(Preparation process)
Components (1)-(6) were heated to 80.degree. C. to melt them, and
then cooled, thereby preparing an ointment.
The dermatologic preparations according to the present invention,
which were prepared in Examples 60-64, had excellent effects of
preventing the occurrence of wrinkles and smoothing or removing
wrinkles and moreover inhibited parakeratosis of the skin,
epidermic hypertrophy and metabolic aberration of lipid and were
excellent in recovery of normal functions and maintenance of
homeostasis.
Preparation Example 40
Preparation of 3-(2-hydroxyethylamino)-1-tetradecylthio-2-propanol
(IIe-1): ##STR117##
A 300-ml flask equipped with a stirrer and dropping funnel was
charged with 61.1 g (1 mol) of ethanolamine and 61 g of ethanol.
While stirring the contents at 80.degree. C., a solution of 14.3 g
(50 mmol) of 1-tetradecylthio-2,3-epoxypropane in 30 g ethanol was
added dropwise over 3 hours. After completion of the dropping, the
resultant reaction mixture was concentrated under reduced pressure,
and the residue was recrystallized from hexane, thereby obtaining
15.8 g (yield: 91%) of the title compound (IIe-1).
Colorless solid.
Melting point: 71.4.degree.-73.2.degree. C.
IR (NaCl, cm.sup.-1): 3364, 2914, 2842, 1464, 1428, 1077, 1038.
NMR (CDCl.sub.3, .delta.): 1.11-1.67(m,24H), 2.47-3.19(m, 11H),
3.62-3.73(m,2H), 3.75-3.90(m, 1H).
Preparation Example 41:
Preparation of
3-[N-(2-hydroxyethyl)-N-methylamino]-2-hydroxy-1-propyl
tetradecanate (IIe-2): ##STR118##
A 100-ml flask equipped with a stirrer and dropping funnel was
charged with 6.01 g (80 mmol) of N-methylethanolamine, 50 ml of
ethanol and 22.8 g (80 mmol) of glycidyl tetradecanate, and the
contents were stirred at 80.degree. C. for 2 hours. The resultant
reaction mixture was concentrated under reduced pressure, and the
residue was purified by chromatography on silica gel, thereby
obtaining 17.5 g (yield: 60.8%) of the title compound (IIe-2).
Pale yellow oil.
IR (NaCl, cm.sup.-1): 3384, 2928, 2852, 1730, 1460, 1174, 1030.
NMR (CDCl.sub.3, .delta.): 0.76-0.92(m,3H), 1.02-1.70(m,22H),
2.14-2.77(m,9H), 3.29(br,2H), 3.54-4.22(m,5H).
Preparation Example 42:
Preparation of
N-[3-(2-hydroxyethylamino)-2-hydroxypropyl]-12-hydroxyoctadecanamide
(IIe-3): ##STR119##
A 200-ml flask equipped with a stirrer was charged with 9.86 g (30
mmol) of ethyl 12-hydroxyoctadecanate, 2.73 g (30 mmol) of
3-amino-1,2-propanediol and 0.58 g (3 mmol) of 28% sodium
methoxide, and the contents were stirred at 80.degree. C. for 1
hour. After cooling the mixture to room temperature, 100 ml of
pyridine and 5.72 g (30 mmol) of p-toluenesulfonyl chloride were
added, followed by stirring at room temperature for 18 hours. The
resultant reaction mixture was added with water and subjected to
extraction with chloroform, followed by concentration under reduced
pressure. Thereafter, the resultant residue was purified by column
chromatography on silica gel, thereby obtaining
N-[3-(4-methylphenylsulfonyloxy)-2-hydroxypropyl]-12-hydroxyoctadecanamide
as an intermediate.
The intermediate obtained above was then transferred to a 200-ml
flask equipped with a stirrer, to which 50 ml or ethanol and 18.3 g
(300 mmol) of ethanolamine were added. The resultant mixture was
stirred at 80.degree. C. for 24 hours. Water was added to the
resultant reaction mixture, followed by extraction with chloroform.
The solvent was distilled off under reduced pressure, and the
resultant residue was then purified by column chromatography on
silica gel, thereby obtaining 4.92 g (yield: 39.4%) of the title
compound (IIe-3).
Pale yellow solid.
Melting point: 97.7.degree.-99.6.degree. C.
IR (NaCl, cm.sup.-1): 3300, 2924, 2848, 1642, 1548, 1468, 1126,
1072.
NMR (CDCl.sub.3 :CD.sub.3 OD=9:1, .delta.): 0.70-0.92(m,3H),
0.98-1.68(m,28), 2.13(t,J=7.5 Hz,2H), 2.53-2.94(m,4H),
3.07-3.89(m,6H).
Example 65
Effect of the amine derivatives on wrinkles formed on hairless mice
by exposure to UVB:
Hairless mice (HR/ICR, aged 9 weeks at the beginning of the
experiment) were each exposed to UVB 3 times a week by using 6
Toshiba healthy lamps, 20SE. The amount of energy was measured by
means of a UV-Radiometer UVR-305/365D manufactured by TOKYO OPTICAL
K.K. The dose upon one exposure was determined to be 1 MED or less,
i.e., 65 mj in an amount of energy of 0.28 mM/cm.sup.2. The
exposure was effected for 20 weeks. After confirming the fact that
the mice had got wrinkles at their backs, they were divided into
groups each consisting of 8 mice. Ethanol solutions separately
containing the amine derivatives (IIe-1), (IIe-2) and (IIe-3) in a
concentration of 0.025% were applied 5 times a week to their
corresponding-groups of mice for 6 weeks in a dose of 80 .mu.l. As
a control, ethanol alone was applied in a dose of 80 .mu.l like the
samples.
After completion of the application, the degree of wrinkles was
visually observed to rank the samples in accordance with the
following standard (wrinkle index). The results are shown in Table
17.
(Wrinkle index; evaluation standard)
1: Wrinkles were completely removed;
2: Wrinkles were scarcely observed;
3: Wrinkles were somewhat observed;
4: Wrinkles were observed to a great extent.
In order to further analyze the particulars of wrinkles, skin
replicas of the size of 1 cm.sup.2 in diameter were gathered from 3
portions of the back in each of the mice using a Hydrophilic
Exaflex hydrophilic vinylsilicone impression material. Each of
these replicas was held horizontally and illuminated at an angle of
30 degrees from the horizontal direction, thereby finding the
proportion of shadows of the wrinkles as an area percent by means
of an image analyzer. The results are shown collectively in Table
17.
TABLE 17 ______________________________________ Area percent by
Amine derivative Wrinkle index image analysis (%)
______________________________________ Control 3.75 .+-. 0.09 6.42
.+-. 0.63 (IIe-1) 3.25 .+-. 0.28 4.04 .+-. 0.39 (IIe-2) 3.00 .+-.
0.20 3.26 .+-. 0.31 (IIe-3) 2.45 .+-. 0.21 1.53 .+-. 0.17
______________________________________
As apparent from the result shown in Table 17, the wrinkles formed
on the backs of the hairless mice can be removed by applying the
amine derivatives (IIe-1), (IIe-2) and (IIe-3) thereto.
Example 66
Inhibitory effect of the amine derivatives on DNA synthesis of
epidermic keratinocyte:
a) Culture of human epidermic keratinocyte:
Human normal keratinocytes (trade name: Epipack) commercially
available from Kurabo Industries Ltd. were purchased and used as
keratinocyteso Incidentally, a medium for human normal
keratinocytes (trade name: K-GM) commercially available from the
said firm was used in the maintenance and subculture of the
cells.
b) Determination of DNA synthesis (thymidine incorporation):
Keratinocytes cultured in a vegetative state in a 24-well plate
were used. A medium in each well was first removed by suction to
add 450 .mu.l of K-GM, to which no pituitary gland extract was
added, to the well, thereby making a medium exchange. Thereafter,
each of the amine derivatives (IIe-1), (IIe-2) and (IIe-3) obtained
in the above synthesis examples was added thereto. Further, 0.2
.mu.Ci/ml of [.sup.3 H] thymidine was subsequently added to
incubate the culture for 4 hours. After the supernatant was then
removed by suction, and the well was washed 3 times with PBS(-),
500 .mu.l of 2N NaOH were added. After the culture was incubated at
37.degree. C. for 10 minutes, an equiamount of 2N HCl was added to
neutralize the culture, and 4 ml of 10% trichloroacetic acid
chilled with ice water were added, followed by leaving at rest for
30 minutes.
Precipitate was collected on a glass filter and then washed 3 times
with 3 ml of 10% trichloroacetic acid chilled with ice water. The
glass filter was washed further once with 3 ml of ethanol chilled
with ice water and then air-dried to measure its radioactivity by a
liquid scintillation counter, thereby calculating the thymidine
incorporation into the cells.
TABLE 18 ______________________________________ Relative amount of
[.sup.3 H] thymidine incorporated (%)* Amine derivative 10 .mu.M
100 .mu.M ______________________________________ (IIe-1) 43.1 7.4
(IIe-2) 29.8 6.7 (IIe-3) 31.0 9.4
______________________________________ *: Indicating the relative
value where a control is assumed to be 100%.
It was apparent from Table 18 that the thymidine incorporation is
markedly reduced by the addition of the amine derivatives, namely,
that the DNA synthesis of the human epidermic keratinocytes is
inhibited. Besides, the human epidermic keratinocytes treated under
the same conditions as described above were observed on the fourth
day. As a result, it was found that most of the cells lead to
insoluble membrane (cornified envelope), i.e., become keratinized.
It is understood from this fact that the amine derivatives
according to the present invention are active in facilitating the
keratinization of epidermis.
Example 67
A W/O type cream having the following composition was obtained in
accordance with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Amine derivative (IIe-3)
0.08 (2) Cholesterol 0.5 (3) Cholesteryl isostearate 1.0 (4)
Polyether-modified silicone 1.5 (5) Cyclic silicone 20.0 (6)
Methylphenylpolysiloxane 2.0 (7) Methylpolysiloxane 2.0 (8)
Magnesium sulfate 0.5 (9) 55% Ethanol 5.0 (10) Carboxymethylchithin
(Chithin Liquid 0.5 HV, product of Ichimaru Pharcos Co., Ltd.) (11)
Purified water Balance ______________________________________
(Preparation process)
Components (1)-(7) were heated to 80.degree. C. to melt them, and
the components (8)-(11) were added to the melt. The resultant
mixture was intimately mixed to prepare a W/O type cream.
Example 68
An O/W type cream having the following composition was obtained in
accordance with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Polyoxyethylene (10)
hardened castor oil 1.0 (2) Sorbitan monostearate 0.5 (3) Sodium
stearoylmethyltaurine 0.5 (4) Cetostearyl alcohol 2.0 (5) Stearic
acid 1.8 (6) Amine derivative (IIe-1) 0.001 (7) Cholesterol 1.5 (8)
Cholesteryl isostearate 1.0 (9) Neopentyl glycol dicaprate 8.0 (10)
Methylpolysiloxane 5.0 (11) Glycerol 5.0 (12) Purified water
Balance ______________________________________
(Preparation process)
Components (1)-(10) were heated to 80.degree. C. to melt them, and
the components (11)-(12) were added to the melt. The resultant
mixture was intimately mixed to prepare an O/W type cream.
Example 69
A sunscreen cream having the following composition was obtained in
accordance with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Amine derivative (IIe-3)
0.05 (2) Silicon-coated zinc oxide 7.0 (3) 2-Ethylhexyl
p-methoxycinnamate 3.0 (4) Cholesteryl isostearate 1.0 (5)
Polyether-modified silicone 2.0 (6) Methylpolysiloxane 5.0 (7)
Cyclic silicone 15.0 (8) Magnesium sulfate 1.0 (9) Glycerol 5.0
(10) Purified water Balance
______________________________________
(Preparation process)
Components (1)-(7) were heated to 80.degree. C. to melt them, and
the components (8)-(10) were added to the melt. The resultant
mixture was intimately mixed to prepare a moisturizing sunscreen
cream.
Example 70
A pack having the following composition was obtained in accordance
with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Amine derivative (IIe-3)
hydrochloride 0.05 (2) Polyvinyl alcohol 15.0 (3) Sodium
carboxymethylcellulose 5.0 (4) Propylene glycol 3.0 (5) Ethanol 8.0
(6) Purified water Balance (7) Perfume base 0.5 (8) Antiseptic,
oxidizing agent q.s. ______________________________________
(Preparation process)
Components (1)-(8) were heated to 70.degree. C. to melt them, and
then cooled, thereby preparing a pack.
Example 71
An ointment having the following composition was obtained in
accordance with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Amine derivative (IIe-2)
0.2 (2) White petrolatum Balance (3) Cholesteryl isostearate 3.0
(4) Liquid paraffin 10.0 (5) Glyceryl ether 1.0 (6) Glycerol 10.0
______________________________________
(Preparation process)
Components (1)-(6) were heated to 80.degree. C. to melt them, and
then cooled, thereby preparing an ointment.
The dermatologic preparations according to the present invention,
which were prepared in Examples 67-71, had excellent effects of
preventing the occurrence of wrinkles and smoothing or removing
wrinkles and moreover inhibited parakeratosis, epidermic
hypertrophy and metabolic aberration of lipid and were excellent in
recovery of normal functions and maintenance of homeostasis.
Preparation Example 43:
Preparation of
N-[2-(2-hydroxyethylamino)ethyl]-12-hydroxyoctadecanamide (IIf-1):
##STR120##
A 30-ml two-necked flask equipped with a stirrer and dropping
funnel was charged with 2.08 g (20 mmol) of aminoethylaminoethanol
and 0.054 g (1 mmol) of sodium methoxide. While heating and
stirring the contents at 80.degree. C. in an N.sub.2 atmosphere, a
solution of 3.29 g (10 mmol) of ethyl 12-hydroxystearate in 10 ml
of THF was added dropwise over 2 hours. The resultant mixture was
stirred further for 13 hours at 80.degree. C. under reduced
pressure. After completion of the reaction, the reaction mixture
was poured into 500 ml of water, and precipitate formed was
purified by flash column chromatography on silica gel, thereby
obtaining 2.85 g (yield: 74%) of the title compound (IIf-1).
Colorless powder.
Melting point: 101.9.degree.-102.4.degree. C.
IR (KBr, cm.sup.-1): 3292, 2920, 2852, 1642, 1552, 1470, 1068.
NMR (CDCl.sub.3, .delta.): 0.90(t,J=6.6 Hz,3H), 1.18-1.71(m,3H),
2.19(t,J=7.8 Hz,2H), 2.70-2.77(m,4H), 3.29-3.68(m,5H).
Preparation Example 44:
A reaction was conducted in the same manner as in Preparation
Example 43 except that methyl 12-hydroxydodecanate was used in
place of ethyl 12-hydroxystearate in Preparation Example 43,
thereby obtaining the following amine derivative (IIf-2).
##STR121##
Pale yellow solid.
Melting point: 73.4.degree.-74.0.degree. C.
IR (KBr, cm.sup.-1): 3284, 2924, 2848, 1628, 1554, 1468, 1388,
1040, 956.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.82-1.74(m,18H), 2.18(t,J=7.4
Hz,2H), 2.75-2.82(m,4H), 3.29-3.69(m,6H).
Example 72
Effect of the amine derivatives on wrinkles formed on hairless mice
by exposure to UVB:
Hairless mice (HR/ICR, aged 9 weeks at the beginning of the
experiment) were each exposed to UVB 3 times a week by using 6
Toshiba healthy lamps, 20SE. The amount of energy was measured by
means of a UV-Radiometer UVR-305/365D manufactured by TOKYO OPTICAL
K.K. The dose upon one exposure was determined to be 1 MED or less,
i.e., 65 mj in an amount of energy of 0.28 mM/cm.sup.2. The
exposure was effected for 20 weeks. After confirming the fact that
the mice had got wrinkles at their backs, they were divided into
groups each consisting of 8 mice. Ethanol solutions separately
containing the amine derivatives (IIf-1) and (IIf-2) in a
concentration of 0.025% were applied 5 times a week to their
corresponding groups of mice for 6 weeks in a dose of 80 .mu.l. As
a control, ethanol alone was applied in a dose of 80 .mu.l like the
samples.
After completion of the application, the degree of wrinkles was
visually observed to rank the samples in accordance with the
following standard (wrinkle index). The results are shown in Table
17.
(Wrinkle index; evaluation standard)
1: Wrinkles were completely removed;
2: Wrinkles were scarcely observed;
3: Wrinkles were somewhat observed;
4: Wrinkles were observed to a great extent.
TABLE 19 ______________________________________ Group Wrinkle index
______________________________________ Control 3.75 .+-. 0.09 Amine
derivative (IIf-1) 2.95 .+-. 0.20 Amine derivative (IIf-2) 2.70
.+-. 0.19 ______________________________________
As apparent from the result shown in Table 19, the wrinkles formed
on the backs of the hairless mice were able to be removed by
applying the amine derivatives (IIf-1) and (IIf-2) thereto.
In order to further analyze the particulars of wrinkles, skin
replicas of the size of 1 cm.sup.2 in diameter were gathered from 3
portions of the back in each of the mice using a Hydrophilic
Exaflex hydrophilic vinylsilicone impression material. Each of
these replicas was held horizontally and illuminated at an angle of
30 degrees from the horizontal direction, thereby finding the
proportion of shadows of the wrinkles as an area percent by means
of an image analyzer. The results are shown in Table 20.
TABLE 20 ______________________________________ Area percent by
Group image analysis (%) ______________________________________
Control 6.42 .+-. 0.63 Amine derivative (IIf-1) 3.10 .+-. 0.31
Amine derivative (IIf-2) 2.31 .+-. 0.20
______________________________________
As apparent from the result shown in Table 20, the wrinkles formed
on the backs of the hairless mice can be removed by applying the
amine derivatives (IIf-1) and (IIf-2) thereto.
Example 73
Inhibitory effect of the amine derivatives on DNA synthesis of
epidermic keratinocyte:
(1) Method:
a) Culture of human epidermic keratinocyte:
Human normal keratinocytes (trade name: Epipack) commercially
available from Kurabo Industries Ltd. were purchased and used as
keratinocytes. Incidentally, a medium for human normal
keratinocytes (trade name: K-GM) commercially available from the
said firm was used in the maintenance and subculture of the
cells.
b) Determination of DNA synthesis (thymidine incorporation):
Keratinocytes cultured in a vegetative state in a 24-well plate
were used. A medium in each well was first removed by suction to
add 450 .mu.l of K-GM, to which no pituitary gland extract was
added, to the well, thereby making a medium exchange. Thereafter,
each of the amine derivatives (IIf-1) and (IIf-2) obtained in the
above Preparation Examples was added thereto. Further, 0.2
.mu.Ci/ml of [.sup.3 H] thymidine was subsequently added to
incubate the culture for 4 hours. After the supernatant was then
removed by suction, and the well was washed 3 times with PBS(-),
500 .mu.l of 2N NaOH were added. After the culture was incubated at
37.degree. C. for 10 minutes, an equiamount of 2N HCl was added to
neutralize the culture, and 4 ml of 10% trichloroacetic acid
chilled with ice water were added, followed by leaving at rest for
30 minutes.
Precipitate was collected on a glass filter and then washed 3 times
with 3 ml of 10% trichloroacetic acid chilled with ice water. The
glass filter was washed further once with 3 ml of ethanol chilled
with ice water and then air-dried to measure its radioactivity by a
liquid scintillation counter, thereby calculating the thymidine
incorporation into the cells.
TABLE 21 ______________________________________ Relative amount of
[.sup.3 H] thymidine incorporated (%)* Amine derivative 10 .mu.M
100 .mu.M ______________________________________ (IIf-1) 7.1 1.5
(IIf-2) 52.3 11.3 ______________________________________ *:
Indicating the relative value where a control is assumed to be
100%.
It was apparent from Table 21 that the thymidine incorporation is
markedly reduced by the addition of the amine derivatives, namely,
that the DNA synthesis of the human epidermic keratinocytes is
inhibited. Besides, the human epidermic keratinocytes treated under
the same conditions as described above were observed on the fourth
day. As a result, it was found that most of the cells lead to
insoluble membrane (cornified envelope), i.e., become keratinized.
It is understood from this fact that the amine derivatives
according to the present invention are active in facilitating the
keratinization of epidermis.
Example 74
A W/O type cream having the following composition was obtained in
accordance with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Amine derivative (IIf-1)
0.08 (2) Cholesterol 0.5 (3) Cholesteryl isostearate 1.0 (4)
Polyether-modified silicone 1.5 (5) Cyclic silicone 20.0 (6)
Methylphenylpolysiloxane 2.0 (7) Methylpolysiloxane 2.0 (8)
Magnesium sulfate 0.5 (9) 55% Ethanol 5.0 (10) Carboxymethylchithin
(Chithin Liquid 0.5 HV, product of Ichimaru Pharcos Co., Ltd.) (11)
Purified water Balance ______________________________________
(Preparation process)
Components (1)-(7) were heated to 80.degree. C. to melt them, and
the components (8)-(11) were added to the melt. The resultant
mixture was intimately mixed to prepare a W/O type cream.
Example 75
An O/W type cream having the following composition was obtained in
accordance with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Polyoxyethylene (10)
hardened castor oil 1.0 (2) Sorbitan monostearate 0.5 (3) Sodium
stearoylmethyltaurine 0.5 (4) Cetostearyl alcohol 2.0 (5) Stearic
acid 1.8 (6) Amine derivative (IIf-2) 0.001 (7) Cholesterol 1.5 (8)
Cholesteryl isostearate 1.0 (9) Neopentyl glycol dicaprate 8.0 (10)
Methylpolysiloxane 5.0 (11) Glycerol 5.0 (12) Purified water
Balance ______________________________________
(Preparation process)
Components (1)-(10) were heated to 80.degree. C. to melt them, and
the components (11)-(12) were added to the melt. The resultant
mixture was intimately mixed to prepare an O/W type cream.
Example 76
A sunscreen cream having the following composition was obtained in
accordance with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Amine derivative (IIf-2)
0.05 (2) Silicon-coated zinc oxide 7.0 (3) 2-Ethylhexyl
p-methoxycinnamate 3.0 (4) Cholesteryl isostearate 1.0 (5)
Polyether-modified silicone 2.0 (6) Methylpolysiloxane 5.0 (7)
Cyclic silicone 15.0 (8) Magnesium sulfate 1.0 (9) Glycerol 5.0
(10) Purified water Balance
______________________________________
(Preparation process)
Components (1)-(7) were heated to 80.degree. C. to melt them, and
the components (8)-(10) were added to the melt. The resultant
mixture was intimately mixed to prepare a moisturizing sunscreen
cream.
Example 77
A pack having the following composition was obtained in accordance
with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Amine derivative (IIf-2)
hydrochloride 0.05 (2) Polyvinyl alcohol 15.0 (3) Sodium
carboxymethylcellulose 5.0 (4) Propylene glycol 3.0 (5) Ethanol 8.0
(6) Purified water Balance (7) Perfume base 0.5 (8) Antiseptic,
oxidizing agent q.s. ______________________________________
(Preparation process)
Components (1)-(8) were heated to 70.degree. C. to melt them, and
then cooled, thereby preparing a pack.
Example 78
An ointment having the following composition was obtained in
accordance with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Amine derivative (IIf-2)
0.075 (2) White petrolatum Balance (3) Cholesteryl isostearate 3.0
(4) Liquid paraffin 10.0 (5) Glyceryl ether 1.0 (6) Glycerol 10.0
______________________________________
(Preparation process)
Components (1)-(6) were heated to 80.degree. C. to melt them, and
then cooled, thereby preparing an ointment.
The dermatologic preparations according to the present invention,
which were prepared in Examples 74-78, had excellent effects of
preventing the occurrence of wrinkles and smoothing or removing
wrinkles and moreover inhibited parakeratosis of the skin,
epidermic hypertrophy and metabolic aberration of lipid and were
excellent in recovery of normal functions and maintenance of
homeostasis.
Preparation Example 79
Effect of amine derivatives on wrinkles formed on hairless mice by
exposure to UVB:
Hairless mice (HR/ICR, aged 9 weeks at the beginning of the
experiment) were each exposed to UVB 3 times a week by using 6
Toshiba healthy lamps, 20SE. The amount of energy was measured by
means of a UV-Radiometer UVR-305/365D manufactured by TOKYO OPTICAL
K.K. The dose upon one exposure was determined to be 1 MED or less,
i.e., 65 mj in an amount of energy of 0.28 mM/cm.sup.2. The
exposure was effected for 20 weeks. After confirming the fact that
the mice had got wrinkles at their backs, they were divided into
groups each consisting of 8 mice. Ethanol solutions (0.025%)
separately containing sphingosine analogues (IIg-1) and (IIg-2)
shown in Table 22 were applied 5 times a week to their
corresponding groups of mice for 6 weeks in a dose of 80 .mu.l. As
a control, ethanol alone was applied in a dose of 80 .mu.l like the
samples.
TABLE 22 ______________________________________ Sphingosine
analogue Structure Synthesis ______________________________________
D-Erythro- spingosine (1a) ##STR122## Synthesized in accordance
with Journal of Organic Chemistry, Vol. 53, 4395(1988). DL-Erythro-
dihydro- sphingosine (1b) ##STR123## Synthesized in accordance with
Journal of Organic Chemistry, Vol. 29, 2783 (1964).
______________________________________
After completion of the application, the degree of wrinkles was
visually observed to rank the samples in accordance with the
following standard (wrinkle index). The results are shown in Table
23.
(Wrinkle index; evaluation standard)
1: Wrinkles were completely removed;
2: Wrinkles were scarcely observed;
3: Wrinkles were somewhat observed;
4: Wrinkles were observed to a great extent.
TABLE 23 ______________________________________ Group Wrinkle index
______________________________________ Control 3.75 .+-. 0.09
Sphingosine (IIg-1) 3.20 .+-. 0.10 Dihydrosphingosine (IIg-2) 3.40
.+-. 0.36 ______________________________________
As apparent from the result shown in Table 23, the wrinkles formed
on the backs of the hairless mice were able to be removed by
applying the sphingosine analogues (IIg-1) and (IIg-2) thereto.
In order to further analyze the particulars of wrinkles, skin
replicas of the size of 1 cm.sup.2 in diameter were gathered from 3
portions of the back in each of the mice using a Hydrophilic
Exaflex hydrophilic vinylsilicone impression material. Each of
these replicas was held horizontally and illuminated at an angle of
30 degrees from the horizontal direction, thereby finding the
proportion of shadows of the wrinkles as an area percent by means
of an image analyzer. The results are shown in Table 24.
TABLE 24 ______________________________________ Area percent by
Group image analysis (%) ______________________________________
Control 6.42 .+-. 0.63 Sphingosine (IIg-1) 5.41 .+-. 0.29
Dihydrosphingosine (IIg-2) 5.11 .+-. 0.28
______________________________________
As apparent from the result shown in Table 28, the wrinkles formed
on the backs of the hairless mice can be removed by applying the
sphingosine analogues (IIg-1) and (IIg-2) thereto.
Example 80
A W/O type cream having the following composition was obtained in
accordance with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) sphingosine (IIg-1) 0.01
(2) Cholesterol 0.5 (3) Cholesteryl isostearate 1.0 (4)
Polyether-modified silicone 1.5 (5) Cyclic silicone 20.0 (6)
Methylphenylpolysiloxane 2.0 (7) Methylpolysiloxane 2.0 (8)
Magnesium sulfate 0.5 (9) 55% Ethanol 5.0 (10) Carboxymethylchithin
(Chithin Liquid 0.5 HV, product of Ichimaru Pharcos Co., Ltd.) (11)
Purified water Balance ______________________________________
(Preparation process)
Components (1)-(7) were heated to 80.degree. C. to melt them, and
the components (8)-(11) were added to the melt. The resultant
mixture was intimately mixed to prepare a W/O type cream.
Example 81
An O/W type cream having the following composition was obtained in
accordance with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Polyoxyethylene (10)
hardened castor oil 1.0 (2) Sorbitan monostearate 0.5 (3) Sodium
stearoylmethyltaurine 0.5 (4) Cetostearyl alcohol 2.0 (5) Stearic
acid 1.8 (6) Dihydrosphingosine (IIg-2) 0.1 (7) Cholesterol 1.5 (8)
Cholesteryl isostearate 1.0 (9) Neopentyl glycol dicaprate 8.0 (10)
Methylpolysiloxane 5.0 (11) Glycerol 5.0 (12) Purified water
Balance ______________________________________
(Preparation process)
Components (1)-(10) were heated to 80.degree. C. to melt them, and
the components (11)-(12) were added to the melt. The resultant
mixture was intimately mixed to prepare an O/W type cream.
Example 82
A sunscreen cream having the following composition was obtained in
accordance with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Sphingosine (IIg-1) 0.2
(2) Silicon-coated zinc oxide 7.0 (3) 2-Ethylhexyl
p-methoxycinnamate 3.0 (4) Cholesteryl isostearate 1.0 (5)
Polyether-modified silicone 2.0 (6) Methylpolysiloxane 5.0 (7)
Cyclic silicone 15.0 (8) Magnesium sulfate 1.0 (9) Glycerol 5.0
(10) Purified water Balance
______________________________________
(Preparation process)
Components (1)-(7) were heated to 80.degree. C. to melt them, and
the components (8)-(10) were added to the melt. The resultant
mixture was intimately mixed to prepare a moisturizing sunscreen
cream.
Example 83
A pack having the following composition was obtained in accordance
with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Sphingosine (IIg-1) 0.05
(2) White petrolatum Balance (3) Cholesteryl isostearate 3.0 (4)
Liquid paraffin 10.0 (5) Glyceryl ether 1.0 (6) Glycerol 10.0
______________________________________
(Preparation process)
Components (1)-(6) were heated to 80.degree. C. to melt them, and
then cooled, thereby preparing an ointment.
Example 84
A pack having the following composition was obtained in accordance
with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Sphingosine (IIg-1)
0.005 (2) Polyvinyl alcohol 15.0 (3) Sodium carboxymethylcellulose
5.0 (4) Propylene glycol 3.0 (5) Ethanol 8.0 (6) Purified water
Balance (7) Perfume base 0.5 (8) Antiseptic, oxidizing agent q.s.
______________________________________
(Preparation process)
Components (1)-(8) were heated to 70.degree. C. to melt them, and
then cooled, thereby preparing a pack.
The dermatologic preparations, which were prepared in Examples
80-84 and comprised the agent for preventing or smoothing wrinkles
according to the present invention as an effective ingredient, had
excellent effects of preventing the occurrence of wrinkles and
smoothing or removing wrinkles.
Preparation Example 45:
Preparation of 1-benzylaminotridecane-2,3-diol (IIh-1): ##STR124##
(1) Preparation of 1,2-epoxy-3-tridecanol:
A 500-ml flask equipped with a stirrer was charged with 23.8 g
(0.12 mol) of 1-tridecen-3-ol, 25.0 g (0.145 mol) of
m-chloroperbenzoic acid and 250 ml of benzene, and the contents
were stirred at room temperature for 48 hours. After completion of
the reaction, 200 ml of hexane. Solids deposited were separated by
filtration, and the solvent was distilled off under reduced
pressure. The resultant residue was purified by column
chromatography on silica gel, thereby obtaining 19.0 g (yield: 74%)
of 1,2-epoxy-3-tridecanol.
(2) Preparation of an amine derivative (IIh-1):
A 500-ml flask equipped with a stirrer was charged with 107 g (1
mol) of benzylamine, to which a solution of 5.2 g (71 mmol) of
1,2-epoxy-3-tridecanol in 170 ml of dioxane was added dropwise over
2 hours. After completion of the dropping, a reaction was conducted
further for 12 hours at 80.degree. C. Dioxane and excess
benzylamine were distilled off under reduced pressure. The
resultant residue was recrystallized from hexane, thereby obtaining
16.4 g (yield: 72%) of the title compound (IIh-1).
Pale yellow solid.
Melting point: 52.6.degree.-53.0.degree. C.
IR (KBr, cm.sup.-1): 3352, 2920, 2854, 1473, 1107, 855, 696. .sup.1
H-NMR (CDCl.sub.3, .delta.): 0.90(t,3H), 1.25-1.55(m,16H),
2.6-3.0(m,2H), 3.5(m,2H), 3.75(m,2H), 7.2(m,5H).
Preparation Example 46:
Preparation of 1-aminotridecane-2,3-diol (IIh-2): ##STR125##
A 200-ml flask equipped with a stirrer was charged with 9.0 g (28
mmol) of the amine derivative (IIh-1) obtained in Preparation
Example 45, 6.0 g (56 mmol) of 2,2-dimethoxypropane and 2 g (20
mmol) of sulfuric acid to react them at room temperature for 20
minutes. After neutralizing the reaction mixture with 2N aqueous
NaOH, extraction with chloroform was conducted, followed by
concentration under reduced pressure. A 300-ml autoclave was
charged with the resultant residue, 1.0 g of 5% Pd/C and 60 ml of
dioxane to conduct hydrogenolysis for 24 hours at room temperature
under a hydrogen pressure of 5 atm. After the catalyst was
separated by filtration, the filtrate was concentrated under
reduced pressure. The resultant residue was charged into a 100-ml
flask equipped with a stirrer, to which 15 ml of 2N HCl and 20 ml
of tetrahydrofuran were added, followed by stirring at room
temperature for 24 hours. The reaction mixture was neutralized with
2N aqueous NaOH, and solids deposited were collected by filtration
and recrystallized from chloroform, thereby obtaining 3.43 g
(yield: 53%) of the title compound (IIh-2).
Colorless solid.
Melting point: 98.degree.-100.degree. C.
IR (KBr, cm.sup.-1): 3376, 3226, 2914, 2848, 1611, 1464, 1110 1080,
981.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.88(m,3H), 1.2-1.55(m,18H),
2.90(m,2H), 3.44(m,1H), 3.71(m,1H).
Preparation Examples 47-48:
The following amine derivatives (IIh-3) and (IIh-4) were obtained
in a manner similar to preparation Examples 45 and 46.
##STR126##
Colorless solid.
Melting point: 113.degree.-117.degree. C.
IR (KBr, cm.sup.-1): 3376, 3304, 3226, 2920, 2848, 1611, 1464 1116,
1080, 984.
.sup.1 H NMR (CDCl.sub.3, .delta.): 0.87(t,J=7 Hz,3H), 1.30(m,28H),
1.50(m,2H), 2.77(dd,J=6.0, 14.0 Hz,1H), 3.07(dd,J=4.0, 14.0 Hz,1H),
3.45(m,1H), 3.60(m,1H). ##STR127##
Colorless solid.
Melting point: 112.5-113.9.degree. C.
IR (KBr, cm.sup.-1): 3376, 3238, 2920, 2848, 1608, 1464, 1332,
987.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.87(t,J=7 Hz,3H), 1.25(m,32H),
1.45(m,2H), 2.76(dd,J=5.6,12.7 Hz,1H), 3.05(dd,J=3.5,12.7 Hz,1H),
3.42(m,1H), 3.60(m,1H).
Preparation Example 49:
Preparation of 3-aminononadecane-1,2-diol (IIh-5): ##STR128##
A 100-ml flask equipped with a stirrer was charged with 5.0 g (14
mmol) of 1,2-isopropylidenedioxy-3-nonadecanol, 10 ml of
triethylamine and 30 ml of dichloromethane. While stirring the
contents at 0.degree. C., 2.4 g (21 mmol) of methanesulfonyl
chloride were added. The resultant mixture was heated to room
temperature and stirred for 2 hours to complete the reaction. The
reaction mixture was added with water and subjected to extraction
with dichloromethane, followed by concentration under reduced
pressure. Thereafter, the resultant residue was purified by column
chromatography on silica gel, thereby obtaining a
methanesulfonylated intermediate. This intermediate was then
transferred to a 100-ml flask equipped with a stirrer, to which 15
ml of dimethylformamide and 3.5 g (54 mmol) of NaN.sub.3 were
added. The contents were stirred at 80.degree. C. for 15 hours.
After cooling, the reaction mixture was added with water and
subjected to extraction with diethyl ether, followed by
concentration under reduced pressure. Thereafter, the resultant
residue was purified by column chromatography on silica gel,
thereby obtaining 4.6 g (86%) of an azide intermediate.
A 200-ml flask equipped with a stirrer was then charged with 0.3 g
(7 mmol) of LiAlH.sub.4 and 50 ml of tetrahydrofuran. While
stirring the contents at room temperature, a tetrahydrofuran
solution of 2.0 g (5.2 mmol) of the azide intermediate obtained
above was added. After stirring the mixture at room temperature for
1 hour, 1.5 g of 5% aqueous KOH were added, and a salt deposited
was separated by filtration. After the solvent was distilled off
under reduced pressure, 12 ml of tetrahydrofuran and 8 ml of 2N HCl
were added to the residue. The mixture was heated and stirred at
50.degree. C. for 1 hour. After cooling the mixture to room
temperature, it was neutralized with 2N aqueous NaOH, and solids
deposited. were collected by filtration and recrystallized from
chloroform, thereby obtaining 0.84 g (yield: 51%) of the title
compound (IIh-5).
Colorless solid.
Melting point: 92.degree.-93.degree. C.
IR (KBr, cm.sup.-1): 3394, 2920, 1608, 1467, 1338, 1065.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.88(t,J=7 Hz,3H), 1.3(m,30H),
2.77(m, 1H), 3.43(ddd,J=3.8,3.8,7.6 Hz,1H), 3.68(dd,J=3.8,11.9
Hz,1H), 3.78(dd,J=3.8,11.9 Hz,1H).
Preparation Example 50:
The following amine derivative (IIh-6) was obtained in a manner
similar to Preparation Example 49. ##STR129##
Colorless solid.
Melting point: 86.degree.-89.degree. C.
IR (KBr, cm.sup.-1): 3388, 2920, 2850, 1608, 1464, 1338, 1062,
1002.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.87(t,J=7 Hz,3H), 1.3(m,26H),
2.78(m,1H), 3.45(ddd,J=4.5,4.5,8.7 Hz,1H), 3.69(dd,J=4.5,12.4
Hz,1H), 3.78(dd,J=4.5,12.4 Hz,1H).
Preparation Example 51:
Preparation of 1-amino-2-octadecanol (IIh-7): ##STR130##
A 500-ml flask equipped with a stirrer was charged with 160 g (1.5
mol) of benzylamine, to which 29 g (0.11 mol) of
1,2-epoxyoctadecane were added dropwise over 3 hours while stirring
at 100.degree. C. Stirring was conducted further for 12 hours at
100.degree. C. Benzyl alcohol was distilled off under reduced
pressure, and the residue was charged into a 500-ml autoclave, to
which 300 ml of ethanol and 10 g of 5% Pd/C were added to conduct
hydrogenolysis for 48 hours at room temperature under a hydrogen
pressure of 5 atm. After the catalyst was separated by filtration,
the filtrate was concentrated under reduced pressure, and the
residue was recrystallized from hexane, thereby obtaining 26.1 g
(yield: 83%) of the title compound (IIh-7).
Colorless solid.
Melting point: 75.2.degree.-76.5.degree. C.
IR (KBr, cm.sup.-1): 3377, 2927, 2855, 1647.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.90(t,J=7 Hz,3H),
1.25-1.50(m,30H), 2.50(dd,J=8.4,13.0 Hz,1H), 2.84(dd,J=3.4,13.0
Hz,1H), 3.56(m,1H).
Preparation Example 52:
Preparation of 2-amino-1-octadecanol (IIh-8): ##STR131##
A 1-liter flask equipped with a stirrer and dropping funnel was
charged with 20 g (70 mmol) of octadecane-1,2-diol, 0.7 g (3.5
mmol) of p-toluenesulfonic acid and 350 ml of dichloromethane.
While stirring the contents at room temperature, 5.9 g (70 mmol) of
dihydropyran were added dropwise. After stirring the mixture at
room temperature for 30 minutes, it was neutralized with
NaHCO.sub.3 and concentrated under reduced pressure, and the
resultant residue was then purified by column chromatography on
silica gel, thereby obtaining 7.5 g (yield[: 29%) of
1-(2-tetrahydropyranyloxy)-2-octadecanol. This compound was charged
into a 200-ml flask equipped with a stirrer, to which 5.1 g (50
mmol) of triethylamine and 50 ml of dichloromethane were added.
Further, 3.8 g (33 mmol) of methanesulfonyl chloride were added at
room temperature with stirring. After the resultant mixture was
stirred at room temperature for 14 hours, the reaction mixture was
added with water and subjected to extraction with dichloromethane,
and the solvent was distilled off under reduced pressure. The
resultant residue and 15 ml of dimethylformamide was charged into a
100-ml flask equipped with a stirrer, to which 5.5 g (83 mmol) of
NaN.sub.3 were added. The contents were stirred at 90.degree. C.
for 1.5 hours. After cooling the reaction mixture to room
temperature, it was added with water and subjected to extraction
with chloroform, followed by concentration under reduced pressure.
Thereafter, the resultant residue was purified by column
chromatography on silica gel, thereby obtaining 7.1 g (yield: 90%)
of an azide intermediate.
A 100-ml flask equipped with a stirrer was charged with 3.4 g (8.6
mmol) of the azide intermediate, 0.02 g (0.1 mmol) of
p-toluenesulfonic acid, 20 ml of methanol and 10 ml of
tetrahydrofuran, and the contents were stirred at 40.degree. C. for
1 hour. After neutralizing the mixture with NaHCO.sub.3, it was
concentrated under reduced pressure. A 200-ml flask equipped with a
stirrer was then charged with 0.58 g (17.2 mmol) of LiAlH.sub.4 and
50 ml of tetrahydrofuran, to which the residue obtained above was
added. The contents were stirred at room temperature for 18 hours.
To the mixture, were added 2.5 g of 5% aqueous KOH, and a salt
deposited was separated by filtration. The filtrate was then
concentrated under reduced pressure, and the resultant residue was
purified by column chromatography on silica gel, thereby obtaining
1.77 g (yield: 72%) of the title compound (IIh-8).
Colorless powder.
Melting point: 80.8.degree.-81.9.degree. C.
IR (KBr, cm.sup.-1): 3340, 2920, 2848, 1470, 1059, 717.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.90(t,3H), 1.25-1.50(m,30H),
2.80(m,1H), 3.25(dd,J=7.0,11.0 Hz,1H), 3.57(dd,J=4.0,11.0
Hz,1H).
Preparation Example 53:
Preparation of 1-(4-morpholino)-3-methyl-branched
isostearyloxy-2-propanol (IIh-9): ##STR132## (in the formula,
.alpha. and .beta. denote numbers satisfying the following
relationship: .alpha.+.beta.=11-17, .alpha.=4-10, .beta.=5-11, and
having a distribution that the peaks of .alpha. and .beta. are 7
and 8, respectively.)
A 200-ml eggplant type flask equipped with a stirrer was charged
with 9.17 g (0.10 mol) of morpholine, 32.6 g (99.8 mmol) of
methyl-branched isostearyl glycidyl ether and 6.40 g of ethanol,
and the contents were heated and stirred at 80.degree. C. in a
nitrogen atmosphere. After 5 hours, the reaction mixture was
concentrated under reduced pressure, and the resultant residue was
purified by column chromatography on silica gel, thereby obtaining
38.0 g (yield: 92%) of the title compound (IIh-9).
Colorless oil.
IR (NaCl, cm.sup.-1): 3468, 2924, 2856, 1456, 1118.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.70-0.98(m,6H),
1.10-1.75(m,29H), 2.28-2.72(m,6H), 3.02-3.55(m,5H),
3.60-4.02(m,5H).
Preparation Example 54:
Preparation of 1-(N,N-dimethylamino)-3-tetradecyloxy-2-propanol
(IIh-10): ##STR133##
A reaction was conducted in the same manner as in Preparation
Example 53 except that an aqueous solution of dimethylamine and
tetradecyl glycidyl ether were used in place of morpholine and
methyl-branched isostearyl glycidyl ether, respectively, in
Preparation Example 53, thereby obtaining an amine derivative
(IIh-10).
Colorless solid.
Melting point: 38.5.degree.-39.4.degree. C.
IR (NaCl, cm.sup.-1): 3428, 2928, 2860, 2780, 1468, 1268, 1122,
1080.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.88(t,J=6.4 Hz,3H),
1.15-1.70(m,24H), 2.05-2.60(m,2H), 2.28(s,6H), 3.30-3.50(m,4H),
3.75-3.95(m,1H).
Preparation Example 55:
Preparation of 1-amino-3-tetradecyloxy-2-propanol (IIh-11):
##STR134##
A reaction was conducted in the same manner as in Preparation
Example 51 except that tetradecyl glycidyl ether was used in place
of 1,2-epoxyoctadecane in Preparation Example 51, thereby
synthesizing an amine derivative (IIh-11).
Colorless solid.
Melting point: 90.2.degree.-91.1.degree. C.
IR (NaCl, cm.sup.-1): 3400, 2920, 2852, 1604, 1428, 1364, 1118.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.84-0.94(m,3H),
1.22-1.42(m,22H), 1.45-1.65(m,2H), 1.65-1.90(br,3H),
2.65-2.88(m,2H), 3.34-3.48(m,4H), 3.64-3.76(m,1H).
Preparation Example 56:
Preparation of N-(3-amino-2-hydroxypropyl)-12-hydroxydodecanamide
(IIh-12): ##STR135##
A 100-ml two-necked flask equipped with a stirrer and dropping
funnel was charged with 9.39 g (104 mmol) of 1,3-diamino-2-propanol
and 0.047 g (0.87 mmol) of sodium methoxide. While heating and
stirring the contents at 80.degree. C. in an N.sub.2 atmosphere, a
THF solution of 4.00 g (17.4 mmol) of methyl 12-hydroxydodecanate
was added dropwise over 2.5 hours. Precipitate formed was washed
with water and recrystallized from ethyl acetate-methanol (4:1
v/v), thereby obtaining 3.80 g (yield: 75%) of the title compound
(IIh-12) as colorless powder.
Colorless solid.
Melting point: 118.7.degree.-119.2.degree. C.
IR (KBr, cm.sup.-1): 3304, 2920, 2854, 1638, 1548, 1467, 1437,
1062.
.sup.1 H-NMR (CD.sub.3 OD, .delta.): 1.21-1.59(m,18H), 2.19(t,J=7.5
Hz,2H), 2.53(dd,J=7.5,13.2 Hz,1H), 2.63(dd,J=4.5,13.2 Hz,1H),
3.20-3.24(m,2H), 3.38-3.77(m,2H), 3.53(t,J=6.5 Hz,2H).
Example 85
Inhibitory effect of the amine derivatives on DNA synthesis of
epidermic keratinocyte:
(1) Method:
a) Culture of human epidermic keratinocyte:
Human normal keratinocytes (trade name: Epipack) commercially
available from Kurabo Industries Ltd. were purchased and used as
keratinocytes. Incidentally, a medium for human normal
keratinocytes (trade name: K-GM) commercially available from the
said firm was used in the maintenance and subculture of the
cells.
b) Determination of DNA synthesis (thymidine incorporation):
Keratinocytes cultured in a vegetative state in a 24-well plate
were used. A medium in each well was first removed by suction to
add 450 .mu.l of K-GM, to which no pituitary gland extract was
added, to the well, thereby making a medium exchange. Thereafter,
each of the amine derivatives (IIh-1)-(IIh-12) obtained in the
above synthesis examples was added thereto. Further, 0.2 .mu.Ci/ml
of [.sup.3 H] thymidine was subsequently added to incubate the
culture for 4 hours. After the supernatant was then removed by
suction, and the well was washed 3 times with PBS(-), 500 .mu.l of
2N NaOH were added. After the culture was incubated at 37.degree.
C. for 10 minutes, an equiamount of 2N HCl was added to neutralize
the culture, and 4 ml of 10% trichloroacetic acid chilled with ice
water were added, followed by leaving at rest for 30 minutes.
Precipitate was collected on a glass filter and then washed 3 times
with 3 ml of 10% trichloroacetic acid chilled with ice water. The
glass filter was washed further once with 3 ml of ethanol chilled
with ice water and then air-dried to measure its radioactivity by a
liquid scintillation counter, thereby calculating the thymidine
incorporation into the cells.
(2) Result:
The relative amounts of the [.sup.3 H] thymidine incorporated at
the time each of the amine derivatives (IIh-1) to (IIh-12) has been
added in amounts of 10 .mu.M and 100 .mu.M are shown in Table
25.
TABLE 25 ______________________________________ Relative amount of
[.sup.3 H] thymidine incorporated (%)* Amine derivative 10 .mu.M
100 .mu.M ______________________________________ (IIh-1) 41.7 13.0
(IIh-2) 24.3 1.6 (IIh-3) 29.6 1.5 (IIh-4) 21.0 2.0 (IIh-5) 26.2 4.6
(IIh-6) 1.9 1.6 (IIh-7) 72.8 1.5 (IIh-8) 38.2 10.1 (IIh-9) 72.1
25.1 (IIh-10) 10.7 0.8 (IIh-11) 8.1 6.6 (IIh-12) 7.1 1.4
______________________________________ *: Indicating the relative
value where a control is assumed to be 100%.
It was apparent from Table 25 that the thymidine incorporation is
markedly reduced by the addition of the amine derivatives, namely,
that the DNA synthesis of the human epidermic keratinocytes is
inhibited. Besides, the human epidermic keratinocytes treated under
the same conditions as described above were observed on the fourth
day. As a result, it was found that most of the cells lead to
insoluble membrane (cornified envelope), i.e., become keratinized.
It is understood from this fact that the amine derivatives
according to the present invention are active in facilitating the
keratinization of epidermis.
Example 86
Effect of the amine derivatives on wrinkles formed on hairless mice
by exposure to UVB:
(1) Hairless mice (HR/ICR, aged 9 weeks at the beginning of the
experiment) were each exposed to UVB 3 times a week by using 6
Toshiba healthy lamps, 20SE. The amount of energy was measured by
means of a UV-Radiometer UVR-305/365D manufactured by TOKYO OPTICAL
K.K. The dose upon one exposure was determined to be 1 MED or less,
i.e., 65 mj in an amount of energy of 0.28 mM/cm.sup.2. The
exposure was effected for 20 weeks. After confirming the fact that
the mice had got wrinkles at their backs, they were divided into
groups each consisting of 8 mice. Ethanol solutions separately
containing the amine derivatives (the samples tested are shown in
Table 26) in a concentration of 0.025% were applied 5 times a week
to their corresponding groups of mice for 6 weeks in a dose of 80
.mu.l. As a control, ethanol alone was applied in a dose of 80
.mu.l like the samples.
After completion of the application, the degree of wrinkles was
visually observed to rank the samples in accordance with the
following standard (wrinkle index). The results are shown in Table
26.
(Wrinkle index)
1: Wrinkles were completely removed;
2: Wrinkles were scarcely observed;
3: Wrinkles were somewhat observed;
4: Wrinkles were observed to a great extent.
(2) In order to further analyze the particulars of wrinkles, skin
replicas of the size of 1 cm.sup.2 in diameter were gathered from 3
portions of the back in each of the mice using a Hydrophilic
Exaflex hydrophilic vinylsilicone impression material. Each of
these replicas was held horizontally and illuminated at an angle of
30 degrees from the horizontal direction, thereby finding the
proportion of shadows of the wrinkles as an area percent by means
of an image analyzer. The results are shown collectively in Table
26.
TABLE 26 ______________________________________ Area percent by
Amine derivative Wrinkle index image analysis (%)
______________________________________ Control 3.75 .+-. 0.09 6.42
.+-. 0.63 (IIh-1) 3.51 .+-. 0.24 4.86 .+-. 0.39 (IIh-3) 3.33 .+-.
0.21 4.29 .+-. 0.31 (IIh-5) 3.25 .+-. 0.28 4.04 .+-. 0.34 (IIh-7)
3.15 .+-. 0.19 3.73 .+-. 0.29 (IIh-8) 3.20 .+-. 0.27 3.88 .+-. 0.29
(IIh-9) 3.19 .+-. 0.20 3.85 .+-. 0.32 (IIh-10) 3.17 .+-. 0.24 3.79
.+-. 0.20 (IIh-12) 3.05 .+-. 0.19 3.41 .+-. 0.32
______________________________________
As apparent from the result shown in Table 26, the wrinkles formed
on the backs of the hairless mice can be removed by applying the
amine derivatives (IIh) thereto.
Example 87
A W/O type cream having the following composition was obtained in
accordance with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Amine derivative (IIh-3)
0.01 (2) Cholesterol 0.5 (3) Cholesteryl isostearate 1.0 (4)
Polyether-modified silicone 1.5 (5) Cyclic silicone 20.0 (6)
Methylphenylpolysiloxane 2.0 (7) Methylpolysiloxane 2.0 (8)
Magnesium sulfate 0.5 (9) 55% Ethanol 5.0 (10) Carboxymethylchithin
(Chithin Liquid 0.5 HV, product of Ichimaru Pharcos Co., Ltd.) (11)
Purified water Balance ______________________________________
(Preparation process)
Components (1)-(7) were heated to 80.degree. C. to melt them, and
the components (8)-(11) were added to the melt. The resultant
mixture was intimately mixed to prepare a W/O type cream.
Example 88
An O/W type cream having the following composition was obtained in
accordance with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Polyoxyethylene (10)
hardened castor oil 1.0 (2) Sorbitan monostearate 0.5 (3) Sodium
stearoylmethyltaurine 0.5 (4) Cetostearyl alcohol 2.0 (5) Stearic
acid 1.8 (6) Amine derivative (IIh-6) 0.05 (7) Cholesterol 1.5 (8)
Cholesteryl isostearate 1.0 (9) Neopentyl glycol dicaprate 8.0 (10)
Methylpolysiloxane 5.0 (11) Glycerol 5.0 (12) Purified water
Balance ______________________________________
(Preparation process)
Components (1)-(10) were heated to 80.degree. C. to melt them, and
the components (11)-(12) were added to the melt. The resultant
mixture was intimately mixed to prepare an O/W type cream.
Example 89
A moisturizing sunscreen cream having the following composition was
obtained in accordance with the below-described preparation
process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Amine derivative
(IIh-10) 0.05 (2) Silicon-coated zinc oxide 7.0 (3) 2-Ethylhexyl
p-methoxycinnamate 3.0 (4) Cholesteryl isostearate 1.0 (5)
Polyether-modified silicone 2.0 (6) Methylpolysiloxane 5.0 (7)
Cyclic silicone 15.0 (8) Magnesium sulfate 1.0 (9) Glycerol 5.0
(10) Purified water Balance
______________________________________
(Preparation process)
Components (1)-(7) were heated to 80.degree. C. to melt them, and
the components (8)-(10) were added to the melt. The resultant
mixture was intimately mixed to prepare a moisturizing sunscreen
cream.
Example 90
A pack having the following composition was obtained in accordance
with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Amine derivative
(IIh-11) hydrochloride 0.01 (2) Polyvinyl alcohol 15.0 (3) Sodium
carboxymethylcellulose 5.0 (4) Propylene glycol 3.0 (5) Ethanol 8.0
(6) Purified water Balance (7) Perfume base 0.5 (8) Antiseptic,
oxidizing agent q.s. ______________________________________
(Preparation process)
Components (1)-(8) were heated to 70.degree. C. to melt them, and
then cooled, thereby preparing a pack.
Example 91
An ointment having the following composition was obtained in
accordance with the below-described preparation process.
______________________________________ (Composition) (wt. %)
______________________________________ (1) Amine derivative
(IIh-12) 0.2 (2) White petrolatum Balance (3) Cholesteryl
isostearate 3.0 (4) Liquid paraffin 10.0 (5) Glyceryl ether 1.0 (6)
Glycerol 10.0 ______________________________________
(Preparation process)
Components (1)-(6) were heated to 80.degree. C. to melt them, and
then cooled, thereby preparing an ointment.
The dermatologic preparations according to the present invention,
which were prepared in Examples 87-91, had excellent effects of
preventing the occurrence of wrinkles and smoothing or removing
wrinkles and moreover inhibited parakeratosis of the skin,
epidermic hypertrophy and metabolic aberration of lipid and were
excellent in recovery of normal functions and maintenance of
homeostasis.
INDUSTRIAL APPLICABILITY
The amine derivatives (I) or (II), or the acid-added salts or
quaternized products thereof and the dermatologic preparations
containing such an effective component according to the present
invention have excellent effects of markedly preventing the
occurrence of wrinkles and smoothing or removing wrinkles, and
moreover possess marked inhibitory effects on parakeratosis, dermal
hypertrophy, metabolic aberration of lipid and the like caused by
the influence of ultraviolet rays and/or other various factors, and
besides recover the normal functions of the skin and contribute to
the maintenance of homeostasis. In particular, they have excellent
effects of preventing dandruff and improving the skin after
sunburn.
The dermatologic preparations according to the present invention
also have an effect of facilitating the keratinization of the skin
and hence have an effect (beautifying effect) of accelerating the
metabolism of melanin which is a causative substance of
pigmentation in the skin caused by sunburn or the like, thereby
improving the pigmentation in the skin.
Accordingly, their application to the skin is effective in the
prevention and removal of wrinkles, improvement in keratinization
and the skin, and the like.
* * * * *